Suksdorfin analogs, compositions thereof, and methods for making and using thereof

ABSTRACT

The present invention is directed to compounds that are analogs of the natural product suksdorfin. Compounds of the present invention include those having Formula IV:                    
     wherein R 20  through R 26 , M and Z are defined herein. The invention is also directed to pharmaceutical compositions and methods of using these compositions for treating retroviral infections.

The present application is a continuation-in-part of U.S. application08/604,305 filed Feb. 21, 1996, now U.S. Pat. No. 5,847,165, which acontinuation-in-part of U.S. application Ser. No. 08/462,280, filed Jun.5, 1995, now U.S. Pat. No. 5,726,204, which is a continuation of U.S.application Ser. No. 08/392,558, filed Feb. 21, 1995, now U.S. Pat. No.5,637,589, which is a continuation in part of U.S. application Ser. No.08/235,852 filed Apr. 29, 1994, now abandoned, all of which are fullyincorporated by reference herein.

The present application was funded under National Institute of Allergiesgrant #AI-33066 such that the U.S. Government has certain rights in thisinvention.

FIELD OF THE INVENTION

The present invention relates to suksdorfin analogs which have beenfound to be useful in treating viral infections, such as HIV infections,as well as to purifying these analogs.

BACKGROUND OF THE INVENTION

Retroviruses

Retroviruses are small, single-stranded positive-sense RNA viruses. Aretroviral particle comprises two identical single-stranded positivesense RNA molecules. Their genome contains, among other things, thesequence for the RNA-dependent DNA polymerase, also known as reversetranscriptase. Many molecules of reverse transcriptase are found inclose association with the genomic RNA in the mature viral particle.Upon entering a cell, this reverse transcriptase produces adouble-stranded DNA copy of the viral genome, which is inserted into thehost cell's chromatin. Once inserted, the viral sequence is called aprovirus. Retroviral integration is directly dependent upon viralproteins. Linear viral DNA termini (the LTRs) are the immediateprecursors to the integrated proviral DNA. There is a characteristicduplication of short stretches of the hosts DNA at the site ofintegration.

Progeny viral genomes and mRNAs are transcribed from the insertedproviral sequence by host cell RNA polymerase II in response totranscriptional, regulatory signals in the terminal regions of theproviral sequence, the long terminal repeats or LTRs. The host cell'sproteins production machinery is used to produce viral proteins, many ofwhich are inactive until processed by virally encoded proteases.Typically, progeny viral particles bud from the cell surface in anon-lytic manner. Retroviral infection does not necessarily interferewith the normal life cycle of an infected cell or organism. However,neither is it always benign with respect to the host organism. Whilemost classes of DNA viruses can be implicated in tumorigenesis,retroviruses are the only taxonomic group of RNA viruses that areoncogenic. Various retroviruses, such as the Human ImmunodeficiencyVirus (HIV), which is the etiological agent responsible for acquiredimmune deficiency syndrome (AIDS) in humans, are also responsible forseveral very unusual diseases of the immune systems of higher animals.

HIV INFECTION AND AIDS

Human Immunodeficiency Virus (HIV), the etiological agent for AIDS(acquired immune deficiency syndrome), is a member of the lentiviruses,a subfamily of retroviruses. Many retroviruses are well-knowncarcinogens. HIV per se is not known to cause cancer in humans or otheranimals, but it does present a formidable challenge to the host. HIVintegrates its genetic information into the genome of the host. Theviral genome contains many regulatory elements which allow the virus tocontrol its rate of replication in both resting and dividing cells. Mostimportantly, HIV infects and invades cells of the immune system; itbreaks down the body's immune system and renders the patient susceptibleto opportunistic infections and neoplasms. The immune defect appears tobe progressive and irreversible, with a high mortality rate thatapproaches 100% over several years.

HIV-1 is trophic and cytopathic for T4 lymphocytes, cells of the immunesystem which express the cell surface differentiation antigen CD4 (alsoknown as OKT4, T4 and leu3). The viral tropism is due to theinteractions between the viral envelope glycoprotein, gp120, and thecell-surface CD4 molecules (Dalgleish, et al., Nature 312:763-767, 1984.These interactions not only mediate the infection of susceptible cellsby HIV, but are also responsible for the virus-induced fusion ofinfected and uninfected T cells. This cell fusion results in theformation of giant multinucleated syncytia, cell death, and progressivedepletion of CD4 cells in AIDS patients. These events result inHIV-induced immunosuppression and its subsequent sequelae, opportunisticinfections and neoplasms.

In addition to CD4+T cells, the host range of HIV includes cells of themononuclear phagocytic lineage (Dalgleish et al., supra), includingblood monocytes, tissue macrophages, Langerhans cells of the skin anddendritic reticulum cells within lymph nodes. HIV is also neurotropic,capable of infecting monocytes and macrophages in the central nervoussystem causing severe neurologic damage. Macrophage/monocytes are amajor reservoir of HIV. They can interact and fuse with CD4-bearing Tcells, causing T cell depletion and thus contributing to thepathogenesis of AIDS.

ANTI-HIV DRUGS

Intensive efforts are currently under way to develop therapies toprevent or intervene in the development of clinical symptoms inHIV-infected individuals. For the most part, efforts have been focusedon the use of nucleoside analogue drugs such as AZT (azidothymidine),and on other dideoxynucleoside derivatives such as ddA, ddT, ddI, andddC. These drugs inhibit the viral enzyme, reverse transcriptase,thereby inhibiting de novo infection of cells. However, once viralinfection has been established within a cell, viral replication utilizeshost cell enzymes. Thus, drugs which inhibit only reverse transcriptasetend to have limited effects. While the spread of free virus within theorganism can be blocked, the mechanisms of syncytium formation andpathogenesis through direct intercellular spread remain. Accordingly,there is a need to provide a new anti-HIV drugs which are not limited toinhibiting reverse transcription as their mechanism of action.

Coumarins and Photoactive Compounds Lomatium suksdorfii (Umbelliferae)is distributed on the United States western coast. The roots of severalLomatium species were used medicinally by the Gosiute Indians who calledthe plant “pia-a-na-tsu” or “great medicine”. The oil and a crystallinesubstance obtained from L. suksdorfii were previously found to exhibitantispasmodic and antibacterial activities (Pettinate et al, J. Amer.Pharm. Assoc., 48:423 (1959).

Powers et al, in U.S. Pat. No. 5,089.634, disclose isocoumarins withcationic substituents for use in inhibiting serine proteases withtrypsin-like, chymotrypsin-like and elastase-like specificity and theirroles as anticoagulant agents and anti-inflammatory agents. Isocoumarinand related heterocyclic compounds represented according to disclosedformula (I) or a pharmaceutically acceptable salt are also disclosed.

Gulliya et al, in U.S. Pat. No. 5,177,073, discloses therapeuticcompositions derived from a pre-activated photoactive compound and aconveyor for destroying tumor or other pathogenic biologicalcontaminants infecting animal body tissues, wherein the conveyor can bea matrix support or an antibody. The activation of the photoactivecompound is used to produce the pre-activated photoactive compoundretaining therapeutic activity subsequent to activation. Suchphotodynamic therapy involves the administration of one or morephotoactive agents to a subject to be treated followed by exposing thespecific target location or target organ of the subject to light. Thephotoactive compound is required to have one or more chromophorescapable of absorbing light energy and capable of being coupled to amatrix support or antibody.

Call and Green, Proc. Montana. Acad. Sci. 16:49 (1956) describe methodsfor activation of pyronocoumarin derivatives.

It is well known that one member of a group of steroisomers has verypotent activity, while other member(s) of the group may be useless forthe same purpose. Often, mixtures of stereoisomers have much loweractivity than is useful. For compounds having stereoisomer, it isimportant to be able to prepare the useful stereoisomer apart from theother stereoisomers, as separation of stereoisomers is often difficultand inefficient.

Sharpless and his co-workers have extensively researched the asymmetricdihydroxylation of olefins since 1988, as reported in Jacobsen et al.,J. Am. Chem. Soc., 1988, 110, 1968-1970. Substantial progress has beenmade in the development of ligands that generate ever higher levels ofenantioselectivityz: Crispino et al., J. Org. Chem., 1993, 58,3785-3786; Amberg et al., J. Org. Chem., 1993, 58, 844-849, Sharpless etal., J. Org. Chem., 1992, 57, 2768-2771. A variety of olefins have beeninvestigated with very good results. Unfortunately, a high level ofenantioselectivity in asymmetric dihydroxylation of a styrene-likeolefin contained in a six-membered ring fused with benzene has not beenreported.

Citation of documents herein is not intended as an admission that any ofthe documents cited herein is pertinent prior art, or an admission thatthe cited document is considered material to the patentability of theclaims of the present application. All statements as to the date orrepresentation as to the contents of these documents is based on theinformation available to the applicant and does not constitute anyadmission as to the correctness of the dates or contents of thesedocuments.

SUMMARY OF THE INVENTION

The present invention is intended to overcome one or more deficienciesof the related art.

The present invention is intended to also provide suksdorfin analogswhich have anti-viral activity and/or anti-retroviral activity, such asanti-HIV activity, in vitro, in situ and/or in vivo, as well aspreparing these suksdorfin analogs.

The present invention provides suksdorfin analogs according to thegeneral formula (G-1) which can be used to inhibit retroviral growth,replication, binding and/or metabolism, and/or to treat a retroviralinfection or related symptoms.

The present invention also provides a process for purifying suksdorfinor suksdorfin analogs having anti-HIV activity from a sample containingsuch a compound, such as, but not limited to, the fruit of the plantLomatium suksdorfi, the method comprising: (a) extracting samplepreparations with hexane to provide active fractions; (b) centrifugingthe active fractions at least once; (c) recovering the supernatant; and(d) purifying the precipitate by silica gel chromatography to recoverthe suksdorfin analog, thereby purifying the protein.

The present invention also provides alternative synthetic methods forobtaining suksdorfin analogs according to formula (G-1), such as atleast one of formula (G-2) and formulae (I) to (XX):

wherein M is O or NH; Z is O, NH or S; R²⁴⁰, and R²⁵⁰ are each H, C₁₋₁₀alkyl, C₁₋₁₀ aryl, alkyl, amide, or CH₂COOR²⁶⁰, where R²⁶⁰ is C₁₋₁₀alkyl or acyl; R²⁰⁰, R²¹⁰, R²²⁰ and R²³⁰ are each H, halogen, hydroxyl,NH₂, NH-alkyl, N-(alkyl)₂, O-alkyl, O-acyl, COCF₃, OCF₃ or CH₂COONH-alkyl; or R²⁰⁰ and R₂₁₀ form C₅-C₁₀ cyclo or heterocyclo optionallysubstituted with one or more halogen, hydroxyl, NH₂, NH-alkyl,N-(alkyl)², O-acyl, O-alkyl, CO, CF₃, OCF₃ or CH₂ COONH-alkyl, andwherein C3 and C4 can be bound by a single or double bond, R²⁴⁰ and R²⁵⁰are either cis-β or cis-α, or trans-3′-α or trans-3′-β oriented.

Analogs according to (G-1) can also be according to formula (G-2), suchas at least one of (I), (III), (IV), (V), (VI), (VII), (X), (XIII),(XIV), (XV) or (XVI):

wherein M is O or NH; X and Y are each CH₂, CO, NHE, S, O, Z is O, NH orS; R³⁴⁰ and R³⁵⁰ are each H, C₁₋₁₀ alkyl, C₁₋₁₀ aryl, alkyl, amide, orCH₂COOR³⁶⁰, where R³⁶⁰ is C₁₋₁₀ alkyl or acyl; R³⁰⁰, R³¹⁰, R³²⁰ and R³³⁰are each H, halogen, hydroxyl, NH₂, NH-alkyl, N-(alkyl)₂, O-alkyl,O-acyl, COCF₃, OCF₃ or CH₂COO NH-alkyl, and wherein C3 and C4 can bebound by a single or double bond, R340 and R³⁵⁰ are either cis-β orcis-α, or trans-3′-α or trans-3′-β oriented, wherein R³⁰⁰, R³¹⁰optionally a form C₅-C₁₀ cyclo or heterocyclo optionally substitutedwith one or more halogen, hydroxyl, NH₂, NH-alkyl, N-(alkyl)², O-acyl,O-alkyl, CO, CF₃, OCF₃ or CH₂ COONH-alkyl.

The present invention is also directed to synthetic methods for makingsuksdorf in analogs according to formula (I) or formula (II), andparticularly to making specific stereoisomers of suksdorfin analogs.

The invention is also directed to a method for treating a subjectinfected with HIV-1 by administering at least one suksdorfin analog,optionally in combination with any one or more of the known anti-AIDStherapeutics or an immunostimulant.

The treatment methods of the invention also include administering to asubject infected with HIV-1 a conjugate of a suksdorf in derivative withsoluble CD4, CD4 derivatives, antibodies specific for CD4, or HIV-codedglycoproteins such as gp120 and gp41, or antibodies thereto.

Other features, advantages, embodiments, aspects and objects of thepresent invention will be clear to those skilled in the areas ofrelevant art, based on the description, teaching and guidance presentedherein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention relates to suksdorfin analogs according to formula(G-1), which are now discovered and/or expected to have anti-retroviralactivity so as to be useful for inhibiting retroviral infection and/orreplication in eukaryotic cells and/or for the treatment of retroviralinfections, such as HIV infection, as well as to methods for preparingspecific useful stereoisomers thereof.

Suksdorfin analogs of the present invention can be according to formula(G-1) or any subset thereof. Non-limiting examples of subgenus' of thepresent invention may include any subset of formulae (I)-(XX), such asformula (G-2), or any other subset as one or more of formula (I)-(XX).High stereospecificity of suksdorfin derivatives is obtained byasymmetric dihydroxylation os seselin.

An example of a suksdorf in analog according to formula (G-1) of thepresent invention is a suksdorfin analog according to formula (I).

wherein R¹, R² are either cis-β or cis-α, or trains-3′-α ortrans-3′-β-oriented, wherein R¹, R², R³ and R⁴ are H, C₁₋₁₀ alkyl, C₁₋₁₀O-acyl, O-alkyl, amide, or CH₂COOR′, where R′ is C₁₋₁₀ alkyl or acyl; R⁵is H, C₁₋₁₀ alkyl, C₁₋₁₀ acyl, CF₃, amide or CH₂COOR⁷, where R⁷ is C₁₋₁₀alkyl, acyl or amide; and R⁶ is H, halogen, C₁₋₁₀ alkyl, orCH₂CH₂NCOOR⁸, where R⁸ is C1-10 alkyl; C3 or C4 can be bound by a singleor double bond; R¹ or R² can be cis-β or cis-α, or trans-3′-α ortrans-3′-β-oriented.

Another non-limiting example of a suksdorf in analog of the presentinvention is a suksdorfin analog according to formula II:

wherein R⁹, R¹⁰, R¹¹ and R¹² are either cis-β or cis-α, or trans-3′-α ortrans-3′-β-oriented, wherein R⁹, R¹⁰, R¹¹ and R¹² are H, C₁₋₁₀, acyl,amide-acyl, amide-alkyl or CH₂OOR′, where R′ is C₁₋₁₀ alkyl or C₁₋₁₀acyl.

Another example of a suksdorf in analog of the present invention is asuksdorf in analog according to formula III.

wherein M is O or NH; X, Y and Z═O, NH or S; R¹³, R¹⁴, R¹⁵, and R¹⁶, areeach H, halogen, OH, O-alkyl, O-acyl, NH₂, NH-alkyl, N-(alkyl)₂, CF₃,OCF₃ or CH₂CONH-alkyl; R¹⁷ and R¹⁸, are each H, C₁₋₁₀ alkyl, C₁₋₁₀ acyl,aryl, COCF₃, amide or CH₂COOR^(19′), where R¹⁹ is C₁₋₁₀ alkyl, C₁₋₁₀acyl, aryl or (+)-camphanoyl or (−)-camphanoyl; and wherein the bondbetween C3 and C4 can be double or single. Configurations at 3′ or 4′can be (R) or (S). R¹⁷ and R¹⁸ can each be cis-β or cis-α or trans-3′-αor trans-3′-β-oriented.

Another example of a suksdorf in analog of the present invention is asuksdorf in analog according to formula IV.

wherein M is O or NH; Z is O, NH or S; R²⁰, R²¹, R²², R²³, R²⁴ are eachH, halogen, OH, O-alkyl, O-acyl, NH₃, NH-alkyl, N-(alkyl)₂, CF₃, OCF₃ orCH₂CONH-alkyl; R¹⁵ and R¹⁶ are each H, C₁₋₁₀ alkyl, C₁₋₁₀acyl, aryl,COCF₃, amide or CH₂COOR¹⁶, where R¹⁶ is C₁₋₁₀ alkyl, C₁₋₁₀ acyl, or arylor (+)-camphanoyl or (−)-camphanoyl; wherein the bond between C3 and C4can be double or single, and wherein the configurations at 3′ or 4′ canbe (R), or (S). R²⁵ and R²⁶ can be oriented cis-β or cis-α, ortrans-3′-β or trans-3′-α.

Another example of a suksdorfin analog of the present invention is asuksdorf n analog according to formula (V):

wherein M is O or NH; X and Z═O, NH or S; R¹⁸, R¹⁹, R³⁰, R³¹ and R³² areeach H, halogen, OH, O-alkyl, O-acyl, NH₂, NH-alkyl, N-(alkyl)₂, CF₃,OCF₃ or CH₂CONH-alkyl; R₃ and R³⁴ are each H, C₁₋₁₀ alkyl, C₁₋₁₀acyl,aryl, COCF₃, amide or CH₂COO R³⁵, where R³⁵ is C₁₋₁₀ alkyl, C₁₋₁₀ acyl,or aryl or (+)-camphanoyl or (−)-camphanoyl and where the bond betweenC3 and C4 can be double or single. Configurations at 3′ or 4′ can be(R), or (S). R³³ and R³⁴ can be oriented cis-β or cis-α or trans-3′-β ortrans-3′-α.

Another example of a suksdorfin analog of the present invention is asuksdorf in analog according to formula (VI).

wherein M is O or NH; X and Z═O, NH or S; R³⁶, R³⁷, R³⁸, and R³⁹, areeach H, halogen, OH, O-alkyl, O-acyl, NH₂, NH-alkyl, N-(alkyl)₃, C₃,OCF₃ or CH₂COHN-aklyl, R⁴⁰ and R⁴¹ are each H, C₁₋₁₀ alkyl, C₁₋₁₀ acyl,aryl, COCF₃, amine or CH₂COOR⁴², where R⁴² is C₁₋₁₀ alkyl, C₁₋₁₀ acyl,or aryl or (+)-camphanoyl or (−)-camphanoyl; wherein the bond between C3and C4 can be double or single, and where the stereo configurations at3′ and 4′ can be (R) or (S). R⁴⁰ and R⁴¹ can be oriented cis-β or cis-α,or trans--3′-β or trans-3′-α.

Another example of a suksdorfin analog of the present invent-on is asuksdorf in analog according to -Formula (VII).

wherein M is O or NH; Z═O, NH or S; R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, are each H,halogen, OH, O-alkyl, O-acyl, NH₂, NH-alkyl, N-(alkyl)₂, CF₃, OCF₃ orCH₂CONH-alkyl; R⁴⁹ and R⁵⁰, are each H, C₁₋₁₀ alkyl, C₁₋₁₀ acyl, aryl,COCF₃, amide or CH₂COOR, where R⁵¹ is C₁₋₁₀ alkyl, C₁₋₁₀ acyl, or arylor (+)-camphanoyl or (−) camphanoyl; wherein the bond between C3 and C4can be double or single and wherein stereo configurations at 3′ or 4′can be (R) or (S). R⁴⁹ and R⁵⁰ can be oriented cis-β or cis-α, ortrans-3′-β or trans-3′-α.

Another example of a suksdorf in analog of the present invention is asuksdorf in analog according to formula (VIII).

wherein M is O or NH; X, Y and Z═O, NH or S; R⁵², R⁵³, R⁵⁴, R⁵⁵ are eachH, halogen, OH, O-alkyl, O-acyl, NH₂, NH-alkyl, N-(alkyl)₂, CF₃, OCF₃ orCH₂CONH-alkyl; R⁵⁶ and R⁵⁷ are each H, C₁₋₁₀ alkyl, C₁₋₁₀acyl, aryl,COCF₃, amide or CH₂COOR⁵⁸, where R⁵⁸ is C₁₋₁₀alkyl, C₁₋₁₀ acyl, or arylor (+)-camphanoyl or (−) -camphanoyl; wherein the bond between C3 and C4can be double or single and wherein stereo configurations at 3′ or 4′can be (R), or (S). R⁵⁶ and R⁵⁷ can be oriented cis-α or cis-β, ortrans-3′-β or trans-3′-α.

Another example of a suksdorf in analog of the present invention is asuksdorfin analog according to formula (IX).

wherein M is O or NH; Z═O, NH or S; R⁵⁹, R⁶⁰, R⁶¹ and R⁶² are each H,halogen, OH, O-alkyl, O-acyl, NH₂, NH-alkyl, N-(alkyl)₃, CF₃, OCF³ orCH₂CONH-alkyl; R⁶³ and R⁶⁴ are each H, C₁₋₁₀ alkyl, C₁₋₁₀ acyl, aryl,COCF3, amide or CH₂COOR⁶⁵, where R⁶⁵ is C₁₋₁₀alkyl, C₁₋₁₀ acyl, or arylor (+) -camphanoyl or (−) -camphanoyl; and wherein the bond between C3and C4 can be double or single and wherein stereo configurations at 3′,4′ can be (R), or (S). R⁶³ and R⁶⁴ can be reoriented cis-α or cis-β, ortrans-3′ -β or trans-3′-α.

Another example of a suksdorfin analog of the present invention is asuksdorfin analog according to formula (X).

wherein M is O or NH; Z═O, NH or S; R₆₆ and R⁶⁷, are each H, halogen,OH, O-alkyl, O-acyl, NH₂, NH-alkyl, N-(alkyl)₂, CF₃, OCF₃ orCH₃CONH-alkyl; R⁶⁸, R⁶⁹, R⁷⁰ are each H, C₁₋₁₀ alkyl, C₁₋₁₀ acyl, aryl,COCF₃, amide or CH₂CCCR⁷¹, where R⁷¹ is C₁₋₁₀ alkyl, C₁₋₁₀ acyl, or arylor (+)-camphanoyl or (−)-camphanoyl, wherein the bond between C3 and C4can be double or single, and wherein stereo configurations at 3′ or 4′can be (R) or (S). R⁶⁸ and R⁶⁹ can be oriented cis-α or cis-β ortrans-3′-β or trans-3′-α.

Another example of a suksdorfin analog of the present invention is asuksdorf in analog according to formula (XI).

wherein M is O or NH; X, Y and Z═S O or S; R⁷² and R⁷³ are each H,halogen, OH, O-alkyl, O-acyl, NH₂, NH-alkyl, N-(alkyl)₂, CF₃, OCF₃ orCH₂CONH-alkyl; R⁷⁴ and R⁷³ are each H, C₁₋₁₀ alkyl, C₁₋₁₀ acyl, aryl,COCF₃, amide or CH₂COOR⁷⁶, where R⁷⁶ is C₁₀ alkyl, C₁₋₁₀ acyl, or arylor (+)-camphanoyl or (−) -camphanoyl, wherein the bond between C3 and C4can be double or single, and wherein stereo configurations at 3′ or 4′can be (R) or (S). R⁷⁴ and R⁷⁵ can be oriented cis-α or cis-β, or trans3′-β or trans-3′-α.

Another example of a suksdorfin analog of the present invention is asuksdorf in analog according to formula (XII)

wherein M is O or NH; Z═O, NH or S; , R⁷⁷, R⁷⁸, R⁸⁰, R⁸¹, R⁸², are eachH, halogen, OH, O-alkyl, O-acyl, NH₂, NH-alkyl, N-(alkyl)₂, CF₃, OCF₃ orCH₂CONH-alkyl; R⁸³ and R⁸⁴, are each H, C₁₋₁₀ alkyl, C₁₋₁₀acyl, aryl,COCF₃, amide or CH₂COOR⁸⁵, where R⁸⁵ is C₁₋₁₀alkyl, C₁₋₁₀acyl, or arylor (+)-camphanoyl or (−)-camphanoyl; wherein the bond between C3 and C4can be double or single, and wherein stereo configurations at 3′ or 4′can be (R) or (S). R⁸³ and R⁸⁴ can be oriented cis-α or cis-β, ortrans-3′-β or trans-3′-α.

Another example of a suksdorfin analog of the present invention is asuksdorfin analog according to formula XIII.

wherein M is O or NH; R⁸⁶, R⁸⁷, R⁸⁸, R⁸⁹, R⁹⁰, R⁹¹, R⁹², R⁹³ are each H,halogen, OH, O-alkyl, O-acyl, NH₂, NH-alkyl, N-(alkyl)₂, CF₃, OCF₃ orCH₂CONH-alkyl; R⁹⁴ and R⁹⁵, are each H, C₁₋₁₀ alkyl, C₁₋₁₀ acyl, aryl,COCF₃, amide or CH₂COOR⁹⁶, where R⁹⁶ is C₁₋₁₀ alkyl, C₁₋₁₀ acyl, or arylor (+) -camphanoyl or (−) -camphanoyl; wherein the bond between C3 andC4 can be double or single and wherein stereo configurations at 3′ or 4′can be (R) or (S). R⁹⁴ and R⁹⁵ can be oriented cis-α or cis-β, ortrans-3′-β or trans-3′-α.

Another example of a suksdorfin analog of the present invention is asuksdorf in analog according to formula (XIV).

wherein M is O or NH; X, Y and Z═O, NH or S; R⁹⁷ and R⁹⁸, are each H,halogen, OH, O-alkyl, O-acyl, NH₃, N-alkyl, N-(alkyl)₂, CF₃, OCF₃ orCH₂CONH-alkyl; R₉₉ and R¹⁰⁰ are each H, C₁₋₁₀ alkyl, C₁₋₁₀ acyl, aryl,COCF₃, amide or CH₂COOR¹⁰¹, where R¹⁰¹ is C₁₋₁₀ alkyl, C₁₋₁₀ acyl, oraryl or (+)-camphanoyl or (−)-camphanoyl group, wherein the bond betweenC3 and C4 can be double or single, and wherein stereo configurations at3′ or 4′ can be (R) or (S). R⁹⁹ and R¹⁰⁰ can be oriented cis-α or CIS-β, or tans-3′-β or trans-3-α.

Another example of a suksdorfin analog of the present invention is asuksdorf in analog according to formula (XV).

wherein M is O or NH; X and Z═O, NH or S; R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, areeach H, halogen, OH, O-alkyl, O-acyl, NH₂, NH-alkyl, N-(alkyl)₂, CF₃,OCF₃ or CH₂CONH-alkyl; R¹⁰⁶ and R¹⁰⁷, are each H, C₁₋₁₀ alkyl, C₁₋₁₀acyl, aryl, COCF₃, amide or CH₂COOR¹⁰⁸, where R¹⁰⁸ is C₁₋₁₀ alkyl, C₁₋₁₀acyl, or aryl or (+)-camphanoyl or (−)-camphanoyl; wherein the bondbetween C3 and C4 can be double or single, and wherein stereoconfigurations at 3′ or 4′ can be R or S. R¹⁰⁶ and R¹⁰⁷ can be orientedcis-α or cis-β, or trans-3′-β or trans-3′-α.

Another example of a suksdorfin analog of the present invention is asuksdorfin analog according to formula (XVI).

wherein M is O or NH; X, Y and Z═O, OH or S; R¹⁰⁹, R¹¹⁰, R¹¹² are eachH, halogen, OH, O-alkyl, O-acyl, NH₂, NH-alkyl, N-(alkyl)₂, CF₃, OCF₃ orCH₂CONH-alkyl; R¹¹³ and R¹¹⁴ are each H, C₁₋₁₀ alkyl, C₁₋₁₀ acyl, aryl,CCCF₃, amide or CH₂COOR₁₁₅, where R¹¹⁵ is C₁₋₁₀ alkyl, C₁₋₁₀ acyl, oraryl or (+)-camphanoyl or (−)-camphanoyl; wherein the bond between C3and C4 can be double or single, and wherein stereo, configurations at 3′or 4′ can be (R) or (S). R¹¹³ and R¹¹⁴ can be oriented, cis-α, cis-β,trans-3′-β or trans-3¹-α.

Another example of a suksdorfin analog of the present invention is asuksdorfin analog according to formula (XVII).

wherein M is O or NH; X, Y and Z═O, NH or S; R¹¹⁶, R¹¹⁷, R¹¹⁸, R¹¹⁹,R¹²⁰, R¹²¹ are each H, halogen, OH, O-alkyl, O-acyl, NH₂, NH-alkyl,N-(alkyl)₂, CF₃, OCF₃ or CH₂CONH-alkyl; R¹²² and R¹²³ are each H, C₁₋₁₀alkyl, C₁₋₁₀ acyl, aryl, COCF₃, amide or C₂COOR¹²⁴, where R¹²⁴ is C₁₋₁₀alkyl, C₁₋₁₀ acyl, or aryl or (+) -camphanoyl or (−)-camphanoyl; whereinthe bond between C3 and C4 can be double or single and wherein stereoconfigurations at 3′ or 4′ can be (R) or (S). R¹³⁰ and R¹³¹ can beoriented cis-α or cis-β or trans-3′-α or trans-3′-β.

Another example of a suksdorfin analog of the present invention is asuksdorfin analog according to for formula (XVIII).

wherein M is O or NH; X, Y and Z═O, NH or S; R¹²⁵, R¹²⁶, R¹²⁷, R¹²⁸ andR¹²⁹ are each H, halogen, OH, O-alkyl, O-acyl, NH₂, NH-alkyl,N-(alkyl)₃, CF₃, OCF₃ or CH₂CONH-alkyl; R¹³⁰ and R¹³¹, are each H, C₁₋₁₀alkyl, C₁₋₁₀acyl, aryl, CCCC₃, amide or CH₂COOR¹³², where R¹³² is C₁₋₁₀alkyl, C₁₋₁₀ acyl, or aryl or (+)-camphanoyl or (−)-camphanoyl; whereinthe bond between C3 and C4 can be double or single and wherein stereoconfigurations at 3′ and 4′ can be (R) or (S). R¹³⁰ and R¹³¹ can beoriented Cis-α, cis-β, trans-3′-β or trans-3′-α.

Another example of a suksdorfin analog of the present invention is asuksdorfin analog according to Formula (XIX).

wherein M is O or NH; Z═O, NH or S; R¹³³, R¹³⁴, R¹³⁵, R¹³⁶, R¹³⁷, R¹³⁹are each H, halogen, OH, O-alkyl, O-acyl, NH₂, NH-alkyl, N-(alkyl)₂,CF₃, OCF₃ or CH₂CONH-alkyl; R¹³⁹ and R¹⁴⁰ are each H, C₁₋₁₀ alkyl,C₁₋₁₀acyl, aryl, COCF₃, amide or CH₂COOR¹⁴¹, where R¹⁴¹ is C₁₋₁₀ alkyl,C₁₋₁₀ acyl, or aryl or (+)-camphanoyl or (−)-camphanoyl; wherein thebond between C3 and C4 can be double or single, and wherein stereoconfigurations at 3′ or 4′ can be (R) or (S). R¹³⁹ and R¹⁴⁰ can beoriented cis-α or cis-β, trans-3′-β or trans-3′-α.

Another example of a suksdorfin analog of the present invention is asuksdorfin analog according to formula (XX).

wherein M is O or NH; Z═O, NH or S; R¹⁴², R¹⁴³ and R¹⁴⁴ are each H,halogen, OH, O-alkyl, O-acyl, NH₂, NH-alkyl, N-(alkyl)₂, CF₃, OCF₃ orCH₂CONH-alkyl; R¹⁴⁵, R¹⁴⁶, and R¹⁴⁷ are each H, C₁₋₁₀ alkyl, C₁₋₁₀ acyl,aryl, COCF₃, amide or CH₂COOR¹⁴⁸, where R¹⁴⁸ is C₁₋₁₀alkyl, C₁₋₁₀ acyl,or aryl or (+)-camphanoyl or (−)-camphanoyl, wherein the bond between C3and C4 can be double or single, and wherein stereo configurations at 3′and 4′ can be (R) or (S). R¹⁴⁶, R¹⁴⁷ and R¹⁴⁸ can be oriented cis-α,cisβ, trans-3′-α, trans-3′-β.

Non-limiting examples of suksdorfin analogs according to formula (I)include the following combinations of R¹, R², R³, R⁴, R⁵ and R⁶.

(I-A) R¹=R²=R³=R⁴=R⁵=R⁶=H

(I-B) R¹=R²=R⁴=R⁵=R⁶=H, R³=O-alkyl

(I-C) R¹=R²=R³=R⁴=R⁶=H, R⁵-alkyl, CF₃, CH₂CO alkyl

(I-D) R¹=R²=R³=R⁴=R⁶=H, R⁵=CH₂CONH-alkyl

(I-E) R¹=R²=O-acyl, R³=R⁴=R⁵=R⁶=H

(I-F) R¹=R²=O-acyl, R³=O-alkyl, R⁴=R⁵=R⁶=H

(I-G) R¹=R²=O-acyl, R³=R⁴=R⁶=H, R⁵=alkyl, CF₃, CH₂COO-alkyl

(I-H) R¹=R²=O-acyl, R³=R⁴=R⁶=H, R⁵=CH₂CONH-alkyl

(I-J) R¹=R²=O-acyl, R³=R⁴=H, R⁵=alkyl, R⁶=halogen or CH₂CH₂N- alkyl

(I-K) R³=R⁴=R⁵=R⁶=R¹=H, R²=-O-alkyl, OCOCH(CH₃)C₂H₅

(I-L) R³=R⁴=R⁵=R⁶=R²=H, R¹=-O-alkyl, OCOCH(CH₃)C₂H₅

(I-M) R³=R⁴=R⁵=R⁶=H, R¹=R²=-O-alkyl

(I-N) R³=R⁴=R⁵=R⁶=H, R¹=R²=OCOCH (CH₃)C₂H₅

(I-O) R³=R⁴=R⁵=R⁶=H, R¹=R²=OCOCH₂CH (CH₃)₂

(I-P) R³=R⁴=R⁵=R⁶=H, R¹=R²=

(I-Q) R³=R⁴=R⁵=R⁶=H, R¹= -O-acyl, OCOCH(CH₃)C₂H₅

(I-R) R³=R⁴=R⁵=R⁶=H, R¹=OCOCH(CH₃)C₂H₅, R²=-O-acyl

(I-S) R³=R⁴=R⁵=R⁶=R²=H, R¹= -O-acyl

(I-T) R³=R⁴=R⁵=R⁶=R²=H, R¹=OCOCH₂CH (CH₃)₂

(I-U) R²=R³=R⁴=R⁵=R⁶=H, R¹=-O-CH₂-φ, where φ=phenyl

(I-V) R²=R³=R⁴=R⁵=R⁶=H, R¹=OMe

(I-W) R²=R³R⁴=R⁵=R⁶=H, R¹=

(I-X) R³=R⁴=R⁵=R⁶=H, R¹=OMe, R²=-O-acyl

(I-Y) R³=R⁴=R⁵=R⁶=H, R¹=

R²=OCOCH₂CH(CH₃)₂

(I-Z) R³=R⁴=R⁵=R⁶=H, R¹=OCH₂-φ R²=-O-acyl

Non-limiting examples of suksdorfin analogs according to formula (II)include the following combinations of R⁹, R¹⁰, R¹¹ and R¹²

(II-A) R⁹=R¹⁰=R¹¹=R¹²=H

(II-B) R¹⁰=R¹¹=R¹²=H, R⁹-alkyl

(II-C) R⁹=R¹⁰=R¹¹=H, R¹²=alkyl, CF₃, or CH₂CO-alkyl

(II-D) R⁹=R¹⁰=R¹¹=H, R¹²=CH₂CONH-alkyl

(II-E) R⁹=R¹⁰=acyl, R¹¹=R¹²=H

(II-F) R⁹=R¹⁰=acyl, R¹¹=-alkyl, R¹²=H

(II-G) R⁹=R¹⁰=acyl, R¹¹=H, R¹²=alkyl, CF₃, CH₂COO-alkyl

(II-H) R⁹=R¹⁰=acyl, R¹¹=H, R¹³=CH₂CONH-alkyl

(II-J) R⁹=R¹⁰=acyl, R¹¹=H, R¹²=alkyl,

(II-K) R¹¹=R¹²=R⁹=H, R¹⁰=alkyl, COCH(CH₃) C₂H₅

(II-L) R¹⁰=R¹¹=R¹²=H, R⁹=alkyl, COCH(CH₃) C₂H₅

(II-M) R₁₁=R¹²=H, R=R¹⁰=acyl

(II-N) R¹¹=R¹²=H, R⁹=R¹⁰=COCH (CH₃) C₂H₅

(II-O) R¹¹R¹²=H, R⁹=R¹⁰=COCH₂CH (CH₃)₂

(II-P) R¹¹=R¹²=H, R⁹=R¹⁰

(II-Q) R¹¹=R¹²=H, R⁹=acyl, R¹⁰=COCH (CH₃) C₂H₅

(II-R) R¹¹=R¹²=H, R⁹=COCH(CH₃)C₂H₅, R¹⁰=acyl

(II-S) R¹¹=R¹²=R¹⁰=H, R⁹=acyl

(II-T) R¹¹=R¹²=R¹⁰=H, R⁹=COCH₂CH(CH₃)₂

(II-U) R¹⁰=R¹¹=R¹²=H, R⁹=CH₂φ, where φ=phenyl

(II-V) R¹⁰=R¹¹=R¹²H, R⁹=Me

(II-W) R¹⁰=R¹¹=R¹²=H, R⁹=

(III-X) R¹⁰=R¹¹=R¹²=H, R⁹=Me, R¹⁰=acyl

(II-Y) R¹⁰=R¹¹=R¹²=H, R⁹=

R¹⁰=COCH₂CH(CH₃)₂

(II-Z) R¹⁰=R¹¹R=R¹²=, R⁹=CH₂-φ, R₁₀=acyl

Non-limiting examples of suksdorfin analogs according to formula (III)include the following combinations R¹³, R¹⁴ of R¹⁵, R¹⁶, R¹⁷, R¹⁸, X, Y,Z and M.

(III-A) R¹³=R¹⁴=R¹⁵=R¹⁶=R¹⁷=R¹⁸=H, M═Y═Z═O, X═NH

(III-B) R¹³=R¹⁴=R¹⁵=R¹⁶=R¹⁸=H, R¹⁷=alkyl, M═Y═Z═O, X═NH

(III-C) R¹⁴=R¹⁵=R¹⁶=R¹⁷=R¹⁸=H, R¹³=O-alkyl, M═Y═Z═O, X═NH

(III-D) R¹⁴=R¹⁵=R¹⁶=R¹⁷=R¹⁸=H, R¹³=O-CH₂CONH-alkyl, M═Y═Z═O, X═NH

(III-E) R¹⁷=R¹⁸=acyl, R¹³=R¹⁴=R¹⁵=R¹⁶=H, M═Y═Z═O, X═NH

(III-F) R¹⁷=R¹⁸=acyl, R¹⁶=O-alkyl, R¹³=R¹⁴=R⁵=H, M═Y═Z═O, X═NH

(III-G) R¹⁷=R¹⁸=acyl, R¹³=O-alkyl, O-CF₃, O-CH₂COO-alkyl, R¹⁴=R¹⁵=R¹⁶=H,M═Y═Z═O, X═NH

(III-H) R¹⁷=R¹⁸=acyl, R¹⁴=R¹⁵=R¹⁶=H, R¹³=O-CH₂CONH-alkyl, M═Y═Z═O, X═NH

(III-J) R¹⁷=R¹⁸=acyl, R¹⁵=R¹⁶H, R¹³=halogen or CH₂CH₂N-alkyl, R¹⁴=alkyl,M═Y═Z═O, X=NH

(III-K) R¹³=R¹⁴=R¹⁵=R¹⁶=R¹⁸=H, R¹⁷=alkyl or COCH(CH₃)C₃H₅, M═Y═Z═O, X═NH

(III-L) R¹³=R¹⁴=R¹⁵=R¹⁶=R¹⁷=H, R¹⁸=alkyl or, COCH(CH₃) C₂H₅, M═Y═Z═O,X═NH

(III-M) R¹³=R¹⁴=R¹⁵=R¹⁶=H, R¹⁷=R¹⁸=acyl, M═Y═Z═O, X═NH

(III-N) R¹³=R¹⁴=R¹⁵=H, R¹⁷=R¹⁸=COCH (CH₃)C₂H₅, M═Y═Z═O, X═NH

(III-O) R¹³=R¹⁴=R¹⁵=R¹⁶=H, R¹⁷=R¹⁸=COCH(CH₃)C₂H₂, M═Y═Z═O, X═NH

(III-P) R¹³=R¹⁴=R¹⁵=R¹⁶=H, R¹⁷R¹⁸=

M═Y═Z═O, X═NH

(III-Q) R¹³=R¹⁴=R¹⁵=R¹⁶=H, R¹⁷=acyl, R¹⁸=COCH(CH₃)C₁H₅, M═Y═Z═O, X═NH

(III-R) R¹³=R¹⁴=R¹⁵=R¹⁶=H, R¹⁸=COCH(CH₃)C₂H₅, R¹⁷=acyl, M═Y═Z═O, X═NH

(III-S) R¹³=R¹⁴=R¹⁵=R¹⁶=R¹⁷=H, R¹⁸=acyl, M═Y═Z═O, X═NH

(III -T) R¹³ R¹⁴=R¹⁵=R¹⁶=R¹⁷=H, R¹³=COCH₂CH(CH₃)₂, M═Y═Z═O═X═NH

(III-U) R¹³=R¹⁴=R¹⁵=R¹⁶=R¹⁷=H, R¹⁸ 32 CH₂φ, where φ=phenyl, M═Y═Z═O,

(III-V) R¹³=R¹⁴=R¹⁵=R¹⁶=R¹⁷=H, R¹⁸=Me, M═Y═Z═O, X═NH

(III-W) R¹³=R¹⁴=R¹⁵=R¹⁶=R¹⁷=H, R¹⁸=

M═Y═Z═O, X═NH

(III-X) R¹³=R¹⁴=R¹⁵=R¹⁶-H, R¹⁸-Me, R¹⁷=acyl, M═Y═Z═O, X═NH

(III-Y) R¹³=R¹⁴R¹⁵=R¹⁶=H, R¹⁸=

R¹⁷=COCH₂CH(CH₃)₂, M═Y═Z═O, X═NH

(III-Z) R¹³=R¹⁴=R¹⁵=R¹⁶=H, R¹⁸=CH₂-φ, R¹⁷=acyl, M═Y═Z═O,, X═NH

Non-limiting examples of suksdorfin analogs according to formula (IV)include the following combinations of R²⁰, R²¹, R²², R^(23, R) ²⁴, R²⁵,R²⁶, Z and M.

(IV-A) R²⁰=R²¹=R²²=R²³=R²⁴=R²⁵=R²⁶=H, M═Z═O, X═NH;.

(IV-B) R²⁰=R²¹=R²²=R²³=R²⁴=R²⁶=H, R²⁵=alkyl, M═Z═O;

(IV-C) R²⁰=R²²=R²³=R²⁴=R²⁵=R²⁶=H, R²¹=O-alkyl, M=2=O;

(IV-D) R²⁰=R²²=R²³=R²⁴=R²⁵=R²⁶=H, R²¹=O-CH₂CONH-alkyl, M═Z═O;

(IV-E) R²⁵=R²⁶=acyl, R²⁰=R²¹R²²=R²³=R²⁴=H, M═Z═O;

(IV-F) R²⁵=R²⁶=acyl, R²⁴=O-alkyl, R²⁰=R²¹=R²²=R²³=H, M═R═O;

(IV-G) R²⁵=R²⁶=acyl, R²⁰=R²¹=R²³=R²⁴=H, R²²=alkyl, CF₃, CH₂COO-alkyl,M═Z═O;

(IV-H) R²⁵=R²⁶=-acyl, R²⁰=R²¹=R²³=R²⁴H, R²²=CH₂CONH-alkyl, M═R═O;

(IV-J) R²⁵=R²⁶=-acyl, R²⁰=R²³=R²⁴=H, R²²=alkyl, R²¹=halogen orCH₂CH₂N-alkyl, M═R═O;

(IV-K) R²⁰=R²¹=R²²=R²³=R²⁴=H, R²⁵=alkyl, COCH(CH₃)C₂H₅, M═R═O;

(IV-L) R²⁰=R²¹=R²²=R²³=R²⁴=H, R²⁶=alkyl, COCH(CH₃)C₂H₅, M═R═O;

(IV-M) R²⁰=R²¹=R²²=R²³=R²⁴=H, R²⁵=R₂₆=acyl, M═R═O;

(IV-N) R²⁰=R²¹=R²²=R²³=R²⁴=H, R²⁵=R²⁶=COCH(CH₃) C₂H₅, M═Z═O;

(IV-O) R²⁰=R²¹=R²²=R²³=R²⁴=H, R²⁵=R²⁶=COCH₂H(CH₃)₂, M═R═O;

(IV-P) R²⁰=R²¹=R²²=R²³=R²⁴=H, R²⁵=R²⁶=

M═Z═O;

(IV-Q) R²⁰=R²¹=R²²=R²³=R²⁴=H, R²⁵=acyl, R²⁶=COCH(CH₃)C₂H₅, M═R═O;

(IV-R) R²⁰=R²¹=R²²=R²³=R²⁴=H, R²⁵=COCH(CH₃)C₂H₅, R²⁵=acyl, M═R═O;

(IV-S) R²⁰=R²¹=R²²=R²³=R²⁴=R²⁶=H, R²⁵=acyl, M═Z═O;

(IV-T) R²⁰=R²¹=R²²=R²⁴=R²⁵=R²⁶=H, R²⁵COCH(CH₃)₂, M═R═O;

(IV-U) R²⁰=R²²=R²³R²⁶=H, R²⁵=CH₂φ, where φ=phenyl, M═Z═O;

(IV-V) R²⁰=R²¹=R²²=R²⁶=H, R²⁵=Me, M═R═O;

(IV-W) R²⁰=R²¹=R²³=R²⁶=H, R²⁵=

M═R═O;

(IV-X) R²⁰=R²¹=R²²=R²³R²⁴=H, R²⁶=Me, R²⁶=acyl, M═Z═O;

(IV-Y) R²⁰=R²¹=R²³=R²⁴=H, R²⁵=

R²⁶=COCH₂CH(CH₃)₂, M═R═O;

(IV-Z) R²⁰=R²¹=R²²R²³=R²⁴==H, R²⁵=CH₂-φ, R²⁶=acyl, M═R═O;

Non-limiting examples of suksdorfin analogs according to formula (V)include the following combinations of R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴,X, Z and M.

(V-A) R²⁸=R²⁹=R³⁰=R³¹=R³²=R³³=R³⁴=H, M═R═O, X═NH

(V-B) R²⁸=R²⁹=R³⁰=R³¹=R³²R³³=H, R³³=alkyl, M═R═O, X═NH

(V-C) R²⁸=R³⁰=R³¹=R³²=R³³=R³⁴=H, R²⁹=O-alkyl, M═R═O, X═NH

(V-D) R²⁸=R³⁰=R³¹=R³²=R³³=R³⁴=H, R²⁹=O-CHCONH-alkyl, M═R═O, X═NH

(V-E) R³³=R³⁴=acyl, R²⁸=R²⁹=R³⁰=R³²=H, M═R═O, X═NH

(V-F) R³³=R³⁴=acyl, R³²=O-alkyl, R²⁸=R²⁹=R³⁰=R³¹=H, M═R═O, X═NH

(V-G) R³³=R³⁴=acyl R³⁰=alkyl, CF₃ or CH₂COO-alkyl, R²⁸=R²⁹=R³¹=R³²=H,M═R═O, X═NH

(V-H) R³³=R³⁴acyl, R²⁸R³⁰R³¹R³²H, R²⁹=O-CH₂CONH-alkyl, M═R═O, X=NH

(V-J) R³³=R³⁴acyl, R²⁸=R³¹=R³²=H, R²⁹=halogen or CH₂CH₂N-alkyl,R³⁰=alkyl, M═Z═O, X═NH

(V-K) R²⁸=R²⁹=R³⁰=R³¹=R³²=R³⁴=H, R³³=alkyl or COCH(CH₃) C₂H₅, M═Z═O,X═NH

(V-L) R²⁸=R²⁹=R³⁰═R³¹=R³⁴═H, R³³=alkyl or, COCH(CH₃)C₃H₅, M═R═O, X═NH

(V-M) R²⁸R²⁹=R³⁰=R³¹=R³²=, R³³=R³⁴=acyl, M═R═O, X═NH

(V-N) R²⁸R²⁹=R³⁰=R³¹=R³²=H, R³³=R³⁴=COCH(CH₃)C₂H₅, M═R═O, X═NH

(V-O) R²⁸=R²⁹=R³⁰=R³¹=R³²=H, R³³=R³⁴=COCH₂CH(CH₃)₂, M═R═O, X═NH

(V-P) R²⁸=R²⁹=R³⁰=R³¹=R³²=H, R³³=R³⁴=

M═Z═O, X═NH

(V-Q) R²⁸=R²⁹=R³⁰=R³²=R³²=H, R³³=acyl, R³⁴=COCH(CH₃)CH₅, M═R═O, X═NH

(V-R) R²⁸=R²⁹=R³⁰R³¹=R³²=H, R³⁴=COCH(CH₃)C₂H₅, R³³=acyl, M═R═O, X═NH

(V-S) R²⁸=R²⁹=R³⁰=R³¹=R³²=R³³=H, R³⁴=acyl, M═Z═O, X═NH

(V-T) R²⁸=R²⁹=R³⁰=R³¹=R³²=R³³ =H, R³⁴=COCH₂CH(CH₃)₂, M═Z═C, X═NH

(V-U) R²⁸=R²⁹=R³¹=R³²=R³³=H, R³⁴=CH₂φ, where φ=phenyl, M═R═O, X═NH

(V-V) R²⁸=R²⁹=R³⁰R³¹=R³²=R³³=H, R³⁴=Me, M═Z═O, X═NH

(V-W) R²⁸=R²⁹=R³⁰=R³¹=R³²=R³³=H, R³⁴=

M═Z═O, X═NH X═NH

(V-X) R²⁸=R²⁹=R³⁰=R³¹=R³³=H, R³³=acyl, M═Z═O, X═NH

(V-Y) R²⁸=R³⁹=R³⁰=R³¹=R³³=H, R³⁴=

R³³=COCH₂CH(CH₃)₂, M═Z═O, Z═NH

(V-Z) R²⁸=R²⁹=R³⁰=R³¹=R³²H, R³⁴=CH₂-φ, R³³=acyl, M═R═O, X═NH

Non-limiting examples of suksdorfin analogs according to formula (VI)include the following combinations of R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, X, Zand M.

(VI-A) R³⁶=R³⁷=R³⁸=R³⁹=R⁴⁰=R⁴¹=H, M═R═O, X═NH

(VI-B) R³⁶=R³⁷=R³⁸=R³⁹=R⁴¹=H, R⁴⁰=alkyl, M═R═O, X═NH

(VI-C) R³⁷=R³⁸=R³⁹=R⁴⁰=R⁴¹=H, R³⁶=O-alkyl, M═R═O, X═NH

(VI-D) R³⁷=R³⁸=R³⁹=R⁴⁰=R⁴¹=H, R³⁶=O-CH₂CONH-alkyl, M═R═O, X═NH

(VI-E) R⁴⁰=R⁴¹=acyl, R³⁹=O-alkyl, R³⁶=R³⁷=R³³=R³⁹=H, M═Z═O, X═NH

(VI-F) R⁴⁰=R⁴¹=acyl, R³⁹=O-alkyl, R³⁶=R³⁷=R³⁸=H, M═R═O, X═NH

(VI-G) R⁴⁰=R⁴¹=acyl, R³⁶=O-alkyl, O-CF₃, O-CH₂COO-alkyl, R³⁷=R³⁸R³⁹=H,M═R═O, X═NH

(VI-H) R⁴⁰=R⁴¹=acyl, R³⁷=R³⁸=R³⁹=H, R³⁶=O—CH₂CONH-alkyl, M═R═O, X═NH

(VI-J) R⁴⁰=R⁴¹=acyl, R³⁸=R³⁹=H, R³⁶=halogen or CH₂CH₂N-alkyl, R³⁷=alkyl,M═R═O, X═NH

(VI-K) R³⁶-R³⁷=R³⁸=R³⁹=R⁴¹=H, R⁴⁰=alkyl or COCH(CH₃)C₂H₅, M═R═O, X═NH

(VI-L) R³⁶=R³⁷R³⁸R³⁹=R⁴⁰=H, R⁴¹=alkyl or, COCH(CH₃)C₂H₅, M═R═O, X═NH

(VI-M) R³⁶=R³⁷=R³⁸=R³⁹=H, R⁴⁰=R⁴¹=acyl, M═R═O, X═NH

(VI-N) R³⁶=R³⁷=R³⁸=R³⁹=H, R⁴⁰=R⁴¹=COCH(CH₃)C₂H₅, M═R═O, X═NH

(VI-O) R³⁶=R³⁷=R³⁸=R³⁹=H, R⁴⁰=R⁴¹=COCH₃CH(CH₃)₂, M═R═O. X═NH

(VI-P) R³⁶=R³⁷R³⁸=R³⁹=H, R⁴⁰=R⁴¹=

M═Z═O, X═NH

(VI-Q) R³⁶R³⁷=R³⁸R³⁹=R=H, R⁴⁰=acyl, R⁴¹=COCH(CH₃)C₂H₅, M═R═O, X═NH

(VI-R) R³⁶=R³⁷R³⁸=R³⁹=H, R⁴¹=COCH(CH₃)C₂H₅, R⁴¹=acyl, M═R═O, X═NH

(VI-S) R³⁶R³⁷R³⁸=R³⁹=R⁴⁰=H, R⁴¹acyl, M═Z═O, X═NH

(VI-T) R³⁶=R³⁷=R³⁸=R³⁹R⁴⁰=H, R⁴¹=COCH₂CH(CH₃)₂, M═Z═O, X═NH

(VI-U) R³⁶=R³⁷=R³⁸=R³⁹=R⁴⁰=H, R⁴¹=CH₂φ, where φ=phenyl, M═R═O, X═NH

(VI-V) R³⁶=R³⁷=R³⁸=R³⁹=R⁴⁰=H, R⁴¹=Me, M═R═O, X═NH

(VI-W) R³⁶=R³⁷R³⁸=R³⁹=R⁴⁰=H, R⁴¹=

M═Z═O X═NH

(VI-X) R³⁶=R³⁷=R³⁸=R³⁹=H, R⁴¹=Me, R⁴⁰=acyl, M═R═O, X═NH

(VI-Y) R³⁶=R³⁷=R³⁸=R³⁹=H, R⁴¹=

R⁴⁰=COCH₂CH(CH₃)₂, M═R═O, X═NH

(VI-Z) R³⁶=R³⁷=R³⁸=R³⁹=H, R⁴¹=CH₂-φ, R⁴⁰=acyl, M═R═O,, X═NH

Non-limiting examples of suksdorfin analogs according to formula (VII)include the following combinations of R⁴², R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹,R⁵⁰, Z and M.

(VII-A) R⁴³=R⁴⁴=R⁴⁵=R⁴⁶=R⁴⁷R⁴⁸=R⁴⁹=R⁵⁰=H, M═R═O;

(VII-B) R⁴³=R⁴⁴=R⁴⁵=R⁴⁶=R⁴⁷=R³⁸=R⁵⁰=H, R⁴⁹¹⁷=alkyl, M═Z═O;

(VII-C) R⁴³=R⁴⁴=R⁴⁶=R⁴⁷=R⁴⁸=R⁴⁹=R⁵⁰=H, R⁴⁵=O-alkyl, M═R═O;

(VII-D) R⁴³=R⁴⁴=R⁴⁵=R⁴⁷=R⁴⁸=R⁴⁹=R⁵⁰=H, R⁴⁵=O-CH₂CONH-alkyl, M═R═O;

(VII-E) R⁴⁹=R⁵⁰=acyl, R⁴³=R⁴⁴=R⁴⁵=R⁴⁶=R⁴⁷=R⁴⁸=H, M═R═O;

(VII-F) R⁴⁹=R⁵⁰=acyl, R⁴⁸=O-alkyl, R⁴³=R⁴⁴=R⁴⁵=R⁴⁶R⁴⁷=H, M═R═O;

(VII-G) R⁴⁹=R⁵⁰=acyl, R⁴⁵=O-alkyl, O-CF₃, O-CH₂COO-alkyl,R⁴³=R⁴⁴=R⁴⁶=R⁴⁷=R⁴⁸=H, M═Z═O;

(VII-H) R⁴⁹=R⁵⁰acyl, R⁴³=R⁴⁴=R⁴⁶=R⁴⁷=R⁴⁸=H, R⁴⁵=O-CH₂CONH-alkyl, M═R═O;

(VII-J) R⁴⁹=R⁵⁰=acyl, R⁴⁷=R⁴⁸=H, R⁴⁵=halogen or CH₂CH₂N-alkyl,R⁴⁶=alkyl, M═Z═O;

(VII-K) R⁴⁵=R⁴⁶=R⁴⁷=R⁴⁸=R⁵⁰=H, R⁴⁹=alkyl or COCH(CH₃C₂H₅, M═R═O;

(VII-L) R⁴⁵=R⁴⁶=R⁴⁷=R⁴⁸=R⁴⁹=H, R⁵⁰=alkyl or, COCH(CH₃C₂H₅, M═R═H;

(VII-M) R⁴⁵=R=R⁴⁷=R⁴⁸=H, R⁴⁹=R⁵⁰=acyl, M═R═O;

(VII-N) R⁴⁵=R⁴⁶=R⁴⁷=R⁴⁸=H, R⁴⁹=R⁵⁰=COCH(CH₃)C₁H₅, M═R═O;

(VII-O) R⁴⁵=R⁴⁶=R⁴⁷=R⁴⁸=H, R⁴⁹=R⁵⁰=COCH₂CH (CH₃)₂, M-Z=O;

(VII-P) R⁴⁵=R⁴⁶=R⁴⁸=H, R⁴⁹=R⁵⁰=

M=Z=O;

(VII-Q) R⁴⁵=R⁴⁶=R⁴⁷=R⁴⁸=H, R⁴⁹=acyl, R⁵°=COCH (CH₃) CH₅ M═R═O;

(VII-R) R⁴⁵=R⁴⁶=R⁴⁷=R⁴⁸=H, R⁴⁹=COCH(CH₃)C₂H₅, R⁴⁹=acyl, M═R═O;

(VII-S) R⁴⁵=R⁴⁶=R⁴⁷=R⁴⁸=H, R⁵⁰=acyl, M═R═O;

(VII-T) R⁴⁵=R⁴⁶=R⁴⁷=R⁴⁸=R⁴⁹=H, R⁵⁰=COCH₂CH(CH₃)₂M═R═O;

(VII-U) R⁴⁵=R⁴⁶=R⁴⁷=R⁴⁸=R⁴⁹=H, R⁵⁰CH₂φ, where φ=phenyl, M═R═O;

(VII-V) R⁴⁵=R⁴⁶=R⁴⁷=R⁴⁸=R⁴⁹=H, R⁵⁰=Me, M═R═O;

(VII-W) R⁴⁵=R⁴⁶=R⁴⁷=R⁴⁸=R⁴⁹H, R⁵⁰=

M═R═O;

(VII-X) R⁴⁵=R⁴⁶=R⁴⁷=R⁴⁸=H, R⁵⁰=Me, R⁴⁹=acyl, M═Z═O;

(VII-Y) R⁴⁵=R⁴⁶=R⁴⁷=R⁴⁸=H, R⁵⁰=

R⁴⁹=COCH₂CH(CH₃)₂, M═Z═O;

(VII-Z) P⁴⁵=H⁴⁶=R⁴⁷=R⁴⁸=H, R⁵⁰=CH₂-φ, R⁴⁹=acyl, M═R═O;

Non-limiting examples of suksdorfin analogs according to formula (VIII)include the following combinations of R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, X, Y, Zand M.

(VIII-A) R⁵²=R⁵³=R⁵⁴=R⁵⁵=R⁵⁶=R⁵⁷=H, M═Y═Z═O, X═NH

(VIII-B) R⁵²=R⁵³=R⁵⁴=R⁵⁵=R⁵⁶=H, R⁵⁶=alkyl, M═Y═Z═O, X═NH

(VIII-C) R⁵²=R⁵⁴=R⁵⁵=R⁵⁶=R⁵⁷=, R⁵³=O-alkyl, M═Y═Z═O, X═NH

(VIII-D) R⁵²=R⁵⁴=R⁵⁵=R⁵⁶=R⁵⁷=H, R⁵³=O-CH₂CONH-alkyl, M═Y═Z═O, X═NH

(VIII-E) R⁵⁶=R⁵⁷=acyl, R⁵²=R⁵³=R⁵⁴=R⁵⁵=H, M═Y═Z═, X═NH

(VIII-F) R⁵⁷=R⁵⁷=acyl, R⁵³=O-alkyl, R⁵²=R⁵³=R⁵⁴=H, M═Y═Z═O, X═NH

(VIII-G) R⁵⁶=R⁵⁷=acyl, R⁵³=O-alkyl, O-CF₃, O-CH₂COO-alkyl,R⁵²=R⁵⁴=R⁵⁵=H, M═Y═Z═O, X═NH

(VIII-H) R⁵⁶=R⁵⁷=acyl, R⁵²R⁵⁴R⁵⁵=H, R⁵³=O-CH₂CONH-alkyl, M═Y═Z═O, X═NH

(VIII-J) R⁵⁶=R⁵⁷=acyl, R⁵²=R⁵³=H, R⁵³=halogen or CH₃CH₃N-alkyl,R⁵⁴=alkyl, M═Y═Z═O, X═NH

(VIII-K) R⁵²=R⁵³=R⁵⁴=R⁵⁵=R⁵⁷=H, R⁵⁶=alkyl or COCH(CH₃)C₂H₅, M═Y-Z═O,X═NH

(VIII-L) R⁵²=R⁵³=R⁵⁴=R⁵⁵=R⁵⁷=H, R⁵⁷=alkyl or, COCH(CH₃)C₂H₅, M═Y═Z═O,X═NH

(VIII-M) R⁵²=R⁵³=R⁵⁴=R⁵⁵=H, R⁵⁶R⁵⁷=acyl, M═Y═Z═O, X═NH

(VIII-N) R⁵²=R⁵³=R⁵⁴=R⁵⁵=H, R⁵⁶=R⁵⁷=COCH(CH₃)C₂H₅, M═Y═Z═O, X═NH

(VIII-O) R⁵²=R⁵³=R⁵⁴=R⁵⁵=H, R⁵⁶=R⁵⁷=COCH₂CH(CH₃)₂, M═Y═Z═O, X═NH

(VIII-P) R⁵²=R⁵³=R⁵⁴=R⁵⁵=H, R⁵⁶=R⁵⁷

M═Y═Z═O, X═NH

(VIII-Q) R⁵²=R⁵³=R⁵⁴=R⁵⁵=H, R⁵⁶=acyl, R⁵⁷=COCH(CH₃)C₂H₅, M═Y═Z═O, X═NH

(VIII-R) R⁵²=R⁵³=R⁵⁴=R⁵⁵=H, R⁵⁷=COCH(CH₃)C₂H₅, R⁵⁶=acyl, M═Y═Z═O, X═NH

(VIII-S) R⁵²=R⁵³=R⁵⁴=R⁵⁵=R⁵⁶=H, R⁵⁷=acyl, M═Y═Z═O, X═NH

(VIII-T) R⁵²=R⁵³=R⁵⁴=R⁵⁵=R⁵⁶=H, R⁵⁷COCH₂CH(CH₃)₂, M═Y═Z═O, X═NH

(VIII-U) R⁵²=R⁵³=R⁵⁴=R⁵⁵=R⁵⁶H, R⁵⁷=CH₂φ, where φ=phenyl, M═Y═Z═O, X═NH

(VIII-V) R⁵²=R⁵³=R⁵⁴=R⁵⁵=R⁵⁶=H, R⁵⁷=Me, M═Y═Z═O, X═NH

(VIII-W) R⁵²=R⁵³=R⁵⁴=R⁵⁵=R⁵⁶=R⁵⁷=C

M═Y═Z═O, X═NH

(VIII-X) R⁵²=R⁵³=R⁵⁵=H, R⁵⁷=Me, R¹⁶=acyl, M═Y═Z═O, X═NH

(VIII-Y) R⁵²=R⁵³=R⁵⁵=H, R⁵⁷H,

R⁵⁶=COCH₂CH(CH₃)₂, M═Y═Z═O, X═NH

(VIII-Z) R⁵²=R⁵³=R⁵⁴=R⁵⁵=H, R⁵⁷=CH₃-φ, R⁵⁶=acyl, M═Y═Z═O,, X═NH

Non-limiting examples of suksdorfin analogs according to formula (IX)include the following combinations of R⁵⁹, R⁶⁰, R⁶¹, R⁶², R⁶³, R⁶⁴, Zand M.

(IX-A) R⁵⁹=R⁶⁰=R⁶¹=R⁶²R⁶³=R⁶⁴H M=Z═O;

(IX-B) R⁵⁹=R⁶⁰=R⁶¹=R⁶²=R⁶⁴=H, R⁶³=alkyl, M═R═O;

(IX-C) R⁶⁰=R⁶¹=R⁶²=R⁶³=R⁶⁴=H, R⁵⁹=O-alkyl, M═Z═O;

(IX-D) R⁶⁰=R⁶¹=R⁶²=R⁶³=R⁶⁴H, R⁵⁹O-CH₂CONH-alkyl, M═R═O;

(IX-E) R⁶³=R⁶¹=acyl, R⁵⁹=R⁶⁰R⁶¹=R⁶²=H, M═Z═O;

(IX-F) R⁶³=R⁶⁴=acyl, R⁶²=O-alkyl, R⁵⁹=R⁶⁰=R⁶¹=H, M═Z═O;

(IX-G) R⁶³=R⁶⁴-acyl, R⁵⁹O-alkyl, O-CF₃, o-CH₂COO-alkyl, R⁶⁰=R⁶¹=R⁶²=H,M═R═O;

(IX-H) R⁶³=R⁶⁴=acyl, R⁶⁰=R⁶¹=R¹²=H, R⁵⁹=O-CH₂CONH-alkyl, M═Z═O;

(IX-J) R⁶³=R⁶⁴=acyl, R⁶¹=R⁶²=H, R⁵⁹=halogen or CH₂CH₂N-alkyl, R⁶⁰=alkyl,M═R═O;

(IX-K) R⁵⁹=R⁶⁰=R⁶¹=R⁶²=R⁶⁴=H, R⁶³=alkyl or COCH(CH₃)C₂H₅, M═Z═O;

(IX-L) R⁵⁹=R⁶⁰=R⁶¹=R⁶²=R⁶³=H, R⁶⁹=alkyl or, COCH(CH₃)C₂H₅, M═R═O;

(IX-M) R⁵⁹=R⁶⁰=R⁶¹=R⁶²=H, R⁶³=R⁶⁴=acyl, M═R═O;

(IX-N) R⁵⁹=R⁶⁰=R⁶¹=R⁶²=H, R⁶³=R⁶⁴=CCH(CH₃)C₂H₅, M═Z═O;

(IX-O) R⁵⁹=R⁶⁰=R⁶¹=R⁶²=H, R⁶³=R⁶=COCH₂CH(CH₃)₂₁ M═R═O;

(IX-P) R⁵⁹=R⁶⁰=R⁶¹=R⁶²=H, R⁶³=R⁶⁴=

M═R═O;

(IX-Q) R⁵⁹=R⁶⁰=R⁶¹=R⁶²=H, R⁶³=acyl, R⁶⁴=COCH(CH₃)C₂H₅, M═R═O;

(IX-R) R⁵⁹=R⁶⁰=R⁶¹=R⁶²=H, R⁶⁴=COCH(CH₃)C₂H₅, R⁶³=acyl, M═R═O;

(IX-S) R⁵⁹=R⁶⁰=R⁶¹=R⁶²=R⁶³H, R⁶⁴=acyl, M═Z═O;

(IX-T) R⁵⁹=R⁶⁰=R⁶¹=R⁶²=R⁶³=H, R⁶⁴=COCH₂CH(CH₃)₂, M═Z═O;

(IX-U) R⁵⁹=R⁶⁰=R⁶¹=R⁶²=R⁶⁴=H, R⁶⁵=CH₂φ, where φ-phenyl, M═Z═O;

(IX-V) R⁵⁹=R⁶⁰=R⁶¹=R⁶²=R⁶³=H, R⁶⁴=Me, M═Z═O;

(IX-W) R⁵⁹=R⁶⁰=R⁶¹=R⁶²=R⁶³=H, R⁶⁴=

M═Z═O;

(IX-X) R⁵⁹=R⁶⁰=R⁶¹=R⁶²=H, R⁶³=Me, R⁶³=acyl, M═Z═O, X═NH

(IX-Y) R⁵⁹=R⁶⁰=R⁶¹=R⁶²=H, R⁶⁴=

R⁶³=COCH₂CH (CH₃)₂, M═Z═O;

(IX-Z) R⁵⁹=R⁶⁰=R⁶⁰=R⁶²=H, R⁶⁴=CH₃-φ, R⁶³=acyl, M═Z═O;

Non-limiting examples of suksdorfin analogs according to formula (X)include the following combinations of R⁶⁰, R⁶⁷, R⁶⁸: R⁶⁹, R⁷⁰, Z and M.

(X-A) R⁶⁶=R⁶⁷=R⁶⁸=R⁶⁹=R⁷⁰=H, M═Z═O;

(X-B) R⁶⁶=R⁶⁷=R⁶⁸=R⁷⁰=H, R⁶⁹=alkyl, M═R═O;

(X-C) R⁶⁶=R⁶⁷=R⁶⁸=R⁶⁹=H, R⁷⁰=O-alkyl, M-Z═O;

(X-D) R⁶⁶=R⁶⁷=R⁶³=R⁶⁹=H, R⁷⁰=O-CH₂CONH-alkyl, M═Z═O;

(X-E) R⁶⁸=R⁶⁹=acyl, R⁶⁶=R⁶⁷=R⁷⁰=H, M═R═O;

(X-F) R⁶⁸=R⁶⁹=acyl, R⁶⁷=O-alkyl, R⁶⁶=R⁷⁰=H, M═R═O;

(X-G) R⁶⁸=R⁶⁹=acyl, R⁷⁰=O-alkyl, O-CF₃, O-CH₂COO-alkyl, R⁶⁶=R⁶⁷=H,M═R═O;

(X-H) R⁶⁸=R⁶⁹=acyl, R⁶⁶=R⁶⁷=H, R⁷⁰=O-CH₂CONH-alkyl, M═R═O;

(X-J) R⁶⁸=R⁶⁹=acyl, R⁶⁷=H, R⁷⁰=halogen or CH₂CH₂N-alkyl, R⁶⁶=alkyl,M═R═O;

(X-K) R⁶⁶=R⁶⁷=R⁶⁹=R⁷⁰=H, R⁶⁸=alkyl or COCH(CH₃)C₂H₅, M═Z═O;

(X-L) R⁶⁶=R⁶⁷=R⁶⁹=R⁷⁰=H, R⁶⁹=alkyl or COCH(CH₃)C₂H₅, M═Z═O;

(X-M) R⁶⁶=R⁶⁷=R⁷⁰=H, R⁶⁹=R⁶⁹=acyl, M═Z═O;

(X-N) R⁶⁶=R⁶⁷=R⁷⁰=H, R⁶⁸=R⁶⁹=COCH(CH₃)C₂H₅, M═Z═O;

(X-O) R⁶⁶=R⁶⁷=R⁷⁰=H, R⁶⁸=R⁶⁹=COCH₂CH(CH₃)₂, M═R═O;

(X-P) R⁶⁶=R⁶⁷=H, R⁶⁸=R⁶⁹=

M═Z═O;

(X-Q) R⁶⁶=R⁶⁷=R⁷⁰=H, R⁶⁸=acyl, R⁶⁹=COCH(CH₃) H₅, M═Z═O;

(X-R) R⁶⁶=R⁶⁷=R⁷⁰=H, R⁶⁹=COCH(CH₃)C₂H₅, R⁶⁸=acyl, M═R═O;

(X-S) R⁶⁶=R⁶⁷=R⁶⁸=R⁷⁰=H, R⁶⁹=acyl, M═Z═O;

(X-T) R⁶⁶=R⁶⁷=R⁶⁸=R⁷⁰=H, R⁶⁹=COCH₂CH(CH₃)₂₁ M═R═O;

(X-U) R⁶⁶=R⁶⁷=R⁶⁸=R⁷⁰=H, R⁶⁹=CH₂φ, where φ-phenyl, M═Z═O;

(X-V) R⁶⁶=R⁶⁷=R⁶⁸=R⁷⁰=H, R⁶⁹=Me, M═Z═O;

(X-W) R⁶⁶=R⁶⁷=R⁶⁸=R⁷⁰=H, R⁶⁹=

M═R═O;

(X-X) R⁶⁶=R⁶⁷=R⁷⁰=H, R⁶⁹=Me, R⁶³=acyl, M═R═O;

(X-Y) R⁶⁶=R⁶⁷=R⁷⁰=H, R⁶⁹=

R⁶⁸=COCH₂CH(CH₃)₂, M═R═O;

(X-Z) R⁶⁶=R⁶⁷=R⁷⁰=H, R⁶⁹=CH₃-φ, R⁶⁸=acyl, M═R═O;

Non-limiting examples of suksdorfin analogs according to formula (XI)include the following combinations of R⁷², R⁷³, R⁷⁴, R⁷⁵, X, Y, Z and M.

(XI-A) R⁷²=R⁷³=R⁷⁴=R⁷⁵=H, M═Y═Z═O, X═NH

(XI-B) R⁷²=R⁷³=R⁷⁵-H, R⁷⁴=alkyl, M═Y═Z═O, X═NH

(XI-C) R⁷²=R⁷³=R⁷⁴=R⁷⁵=H, R⁷²=alkyl, M═Y═Z═O, X═NH

(XI-D) R⁷²=R⁷⁴=R⁷⁵=H, R⁷²-alkyl, M═Y═Z═O, X═NH

(XI-E) R⁷⁴=R⁷⁵=acyl, R⁷²=R⁷³=H, M═Y═Z═O, X═NH

(XI-F) R⁷⁴=R⁷⁵=acyl, R⁷³=O-alkyl, R⁷²=H, M═Y═Z═O, X═NH

(XI-G) R⁷⁴=R⁷⁵=acyl, R⁷=O-alkyl, O-CF₃, O-CH₂COO-alkyl, R⁷³=H, M═Y═Z═O,X═NH

(XI-H) R⁷⁴=R⁷⁵=acyl, R⁷³H, R⁷²=O-CH₂CONH-alkyl, M═Y═Z═O, X═NH

(XI-J) R⁷⁴=R⁷⁵=acyl, R⁷²=halogen or CH₂CH₂N-alkyl, R⁷³=alkyl, M═Y═Z═O,X═NH

(XI-K) R⁷²=R⁷³R⁷⁵=H, R⁷⁴=alkyl or COCH(CH₃)C₂H₅, M═Y═Z═O, X═NH

(XI-L) R⁷²=R⁷³=R⁷⁴=H, R⁷⁵=alkyl or, COCH(CH₃)CH₅, M═Y═Z═O, X═NH

(XI-M) R⁷²=R⁷³=H, R⁷⁴=R⁷⁵=acyl, M═Y═Z═O, X═NH

(XI-N) R⁷²=R⁷³=H, R⁷⁴=R⁷⁵=COCH(CH₃)C₂H₅, M═Y═Z═O, X═NH

(XI-O) R⁷²=R⁷³=H, R⁷⁴=R⁷⁵=COCH₂CH(CH₃)₂, M═Y═Z═O, X═NH

(XI-P) R⁷²=R⁷³=H, R⁷⁴=R⁷⁵=

M═Y═Z═O, X═NH

(XI-Q) R⁷²=R⁷³=H, R⁷⁴=acyl, R⁷⁵=COCH(CH₃)C₂H₅, M═Y═Z═O, X═NH

(XI-R) R⁷²=R⁷³=H, R⁷⁵=COCH(CH₃)C₂H₅, R⁷⁴=acyl, M═Y═Z═O, X═NH

(XI-S) R⁷²=R⁷³=R⁷⁴=H, R⁷⁵=acyl, M═Y═Z═O, X═NH

(XI-T) R⁷²=R⁷³=R⁷⁴=H, R⁷⁵=COCH₂CH(CH₃)₂, MY═Z═O, X═NH

(XI-U) R⁷²=R⁷³=R⁷⁴=H, R⁷⁵=CH₂φ, where φ-phenyl, M═Y═Z═O, X═NH

(XI-V) R⁷²=R⁷³=R⁷⁴=H, R⁷⁵=Me, M═Y═Z═O, X═NH

(XI-W) R⁷²=R⁷³=R⁷⁴=H, R⁷⁵=

M═Y═Z═O, X═NH

(XI-X) R⁷²=R⁷³=H, R⁷⁵=Me, R⁷⁴=acyl. M═Y═Z═O, X═NH

(XI-Y) R⁷²=R⁷³H, R⁷⁵=,

R⁷⁴=COCH₂CH(CH₃)₂,

(XI-Z) R⁷²=R⁷³=H, R⁷⁵=CH₂-φ, R⁷⁴acyl, M═Y═Z═O; X═NH

Non-limiting examples of suksdorfin analogs according to formula (XII)include the following combinations of R⁷⁷, R⁷⁸, R⁷⁹, R⁸⁰, R⁸¹, R⁸², R⁸³,R⁸⁴, Z and M.

(XII-A) R⁷⁷=R⁷⁸=R⁷⁹=R⁸⁰=R⁸¹=R⁸²=R⁸³=R⁸⁴=H, M═R═O;

(XII-B) R⁷⁷=R⁷⁸=R⁷⁹=R⁸⁰=R⁸¹=R⁸²=R⁸³=H, R⁸³=alkyl, M═R═O;

(XII-C) R⁷⁷=R⁷⁸=R⁸⁰=R⁸¹=R⁸²=R⁸³=R⁸⁴=H, R⁷⁹=O-alkyl, M═R═O;

(XII-D) R⁷⁷=R⁷⁸=R⁸⁰=R⁸¹=R⁸²=R⁸³=R⁸⁴=H, R⁷⁹=O-CH₂CONH-alkyl, M═R═O;

(XII-E) R⁸³=R⁸⁴=acyl, R⁷⁷=R⁷⁸=R⁷⁹=R⁸⁰R⁸¹=R⁸²=H, M═Z═O;

(XII-F) R⁸³=R⁸⁴=acyl, R⁸²=O-alkyl, R⁷⁷=R⁷⁸=R⁷⁹=R⁸⁰=R⁸¹=H, M═R═O;

(XII-G) R⁸³=R⁸⁴=acyl, R⁷⁹=O-alkyl, O-CF₃, O-CH₂COO-alkyl.R⁷⁷=R⁷⁸=R⁸⁰=R⁸¹=R⁸²=H, M═R═O;

(XII-H) R⁸³=R⁸⁴=acyl, R⁷⁷=R⁷⁸=R⁸⁰=R⁸¹=R⁸²=H, R⁷⁹=O-CHCONH-alkyl, M═R═O;

(XII-J) R⁸³=R⁸⁴=acyl, R⁸¹=R⁸²=H, R⁷⁹=halogen or CH₂CH₂N-alkyl,R⁷⁷=R⁷⁸=R⁸⁰=alkyl, M═R═O;

(XII-K) R⁷⁷=R⁷⁸=R⁷⁹=R⁸⁰=R⁸¹=R⁸²=R⁸⁴=H, R⁸³=alkyl or COCH(CH₃)C₂H₅,M═R═O;

(XII-L) R⁷⁷=R⁷⁸=R⁷⁹=R⁸⁰=R⁸¹=R⁸²=R⁸³=H, R⁸⁴-alkyl or, COCH(CH₃)C₂H₅M═R═O;

(XII-M) R⁷⁷=R⁷⁸=R⁷⁹=R⁸⁰=R⁸¹=R⁸²=H, R⁸³=R⁸⁴=acyl, M═R═O;

(XII-N) R⁷⁷=R⁷⁸=R⁷⁹=R⁸⁰=R⁸¹=R⁸²=H, R⁸³=R⁸⁴=COCH(CH₃)C₂H₅, M═R═O;

(XII-O) R⁷⁷=R⁷⁸=R⁷⁹R⁸⁰=R⁸¹=R⁸²=H, R⁸³=R⁸⁴=COCH₂CH(CH₃)₂, M═R═O;

(XII-P) R⁷⁷=R⁷⁸=R⁷⁹=R⁸⁰=R⁸¹=R⁸²=H, R⁸³=R⁸⁴=

M═R═O;

(XII-Q) R⁷⁷=R⁷⁸=R⁷⁹R⁸⁰=R⁸¹=R⁸²=H, R⁸³=acyl, R⁸⁴=COCH(CH₃)C₂H₅, M═Z═O;

(XII-R) R⁷⁷=R⁷⁸=R⁷⁹=R⁸⁰=R⁸¹=R⁸²=H, R⁸⁴=COCH(CH₃)C₂H₅, R⁸⁴=acyl, M═R═O;

(XII-S) R⁷⁷=R⁷⁸=R⁷⁹=R⁸⁰=R⁸¹=R⁸²=R⁸³=H, R⁸³Z=acyl, M═R═O;

(XII-T) R⁷⁷=R⁷⁸=R⁷⁹=R⁸⁰=R⁸¹=R⁸²=R⁸³=H, R⁸⁴=COCH₂CH(CH₃)₂, M═R═O;

(XII-U) R⁷⁷=R⁷⁸=R⁷⁹=R⁸⁰=R⁸¹=R⁸²=R⁸³=H, R⁸⁴=CH₁φ, where φ=phenyl, M═Z═O;

(XII-V) R⁷⁷=R⁷⁸=R⁷⁹=R⁸⁰=R⁸¹=R⁸²=H, R⁸⁴=Me, M═Z═O;

(XII-X) R⁷⁷=R⁷⁸=R⁷⁹=R⁸⁰=R⁸¹=R⁸²=R⁸³=H, R⁸⁴=

M═Z═O;

(XII-X) R⁷⁷=R⁷⁸=R⁷⁹=R⁸⁰=R⁸¹=R⁸²=H, R⁸⁴=Me, R⁸³=acyl, M═Z═O;

(XII-Y) R⁷⁷=R⁷⁸=R⁷⁹=R⁸⁰=R⁸¹=R⁸²=H,

R⁸³=COCH₂CH(CH₃)₂, M═Z═O;

(XII-Z) R⁷⁷=R⁷⁸=R⁷⁹=R⁸⁰=R⁸¹=R⁸²=H, R⁸⁴=CH₂-φ, R⁸³=acyl, M=Z=O;

Non-limiting examples of suksdorfin analogs according to formula (XIII)include the following combinations of R⁸⁶, R⁸⁷, R⁸⁸, R⁸⁹, R⁹⁰, R⁹¹, R⁹²,R⁹³, R⁹⁴, R⁹⁵ and M.

(XIII-A) R⁸⁶=R⁸⁷=R⁸⁸=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=R⁹³=R⁹⁴=R⁹⁵=H, M═O;

(XIII-B) R⁸⁶=R⁸⁷=R⁸⁸=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=R⁹³=R⁹⁵=H, R⁹⁴=alkyl, M═O;

(XIII-C) R⁸⁶=R⁸⁷=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=R⁹³=R⁹⁴=H, R⁸⁸=O-alkyl, M═O;

(XIII-D) R⁸⁶=R⁸⁷=R⁸⁸=R⁸⁹=R⁹¹=R⁹²=R⁹³=R⁹⁴=R⁹⁵=H, R⁸⁸O-CH₂CON-alkyl, M═O;

(XIII-E) R⁹⁴=R⁹⁵=acyl, R⁸⁶=R⁸⁷=R⁸⁸=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=R⁹³=H, M═Y═Z═O;

(XIII-F) R⁹⁴=R⁹⁵=acyl, R⁹³=O-alkyl R⁸⁶=R⁸⁷=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=H, M═O;

(XIII-G) R⁹⁴=R⁹⁵=acyl, R⁸⁸=O-alkyl, O-CF₃, O-CH₂COO-alkyl,R⁸⁶=R⁸⁷=R⁸⁹==R⁹⁰=R⁹¹=R^(92=R93)=H, M═O;

(XIII-H) R⁹⁴=R⁹⁵=acyl, R⁸⁶=R⁸⁷=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=R⁹³=H,R⁸⁸=O-CH₂CONH-alkyl, M═O;

(XIII-J) R⁹⁴=R⁹⁵=acyl, R⁸⁶=R⁸⁷=R⁹⁰=R⁹¹=R⁹²=R⁹³=H, R⁸⁸=halogen orCH₂CH₂N-alkyl, R⁸⁹=alkyl, M═O;

(XIII-K) R⁸⁶=R⁸⁷=R⁸⁸=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=R⁹³=H, R⁹⁴=alkyl or COCH(CH₃)C₂H₅,M═O;

(XIII-L) R⁸⁶=R⁸⁷=R⁸⁸=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=R⁹³=R⁹⁴=H, R⁹⁵=alkyl or,COCH(CH₃)C₂H₅, M═O;

(XIII-M) R⁸⁶=R⁸⁷=R⁸⁸=R⁸⁹=R⁹⁰=R⁹¹=R⁹²R⁹³=H, R⁹⁴=R⁹⁵=acyl, M═O;

(XIII-N) R⁹⁶=R⁸⁷=R⁸⁸=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=R⁹³=H, R⁹⁴=R⁹⁵=COCH(CH₃)C₂H₅, M═O;

(XIII-O) R⁸⁶=R⁸⁷=R⁸⁸=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=R⁹³=H, R⁹⁴=R⁹⁴=COCH₂CH(HC₃)₂, M═O;

(XIII-P) R⁸⁶=R⁸⁷=R⁸⁸=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=R⁹³=H, R⁹⁴=R⁹⁵=

M═O;

(XIII-Q) R⁸⁶=R⁸⁷=R⁸⁸=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=R⁹³=H, R⁹⁴-acyl, R⁹⁵=COCH(CH₃)C₂H₅,M═O;

(XIII-R) R⁸⁶=R⁸⁷=R⁸⁸=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=R⁹³=H, R⁹⁵=COCH(CH₃)C₂H₅, R⁹⁴=acyl,M═O;

(XIII-S) R⁸⁶=R⁸⁷=R⁸⁸=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=R⁹³=R⁹⁴=H. R⁹⁵=acyl, M═O;

(XIII-T) R⁸⁶=R⁸⁷=R⁸⁸=R⁸⁹=R⁹⁰=R⁹¹=R⁹²R⁹³=R⁹⁴=H, R⁹⁵=COCH₂CH(CH₃)₂, M═O;

(XIII-U) R⁸⁶=R⁸⁷=R⁸⁸=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=R⁹³=R⁹⁴=H, R⁹⁵=CH₂φ, whereφ=phenyl, M═O;

(XIII-V) R⁸⁶=R⁸⁷'R⁸⁸=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=R⁹³=R⁹⁴=H, R⁹³=Me, M═O;

(XIII-W) R⁸⁶=R⁸⁷=R⁸⁸=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=R⁹³=R⁹⁴=H, R⁹⁵=C-

M═O;

(XIII-X) R⁸⁶=R⁸⁷=R⁸⁸=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=R⁹³=H, R⁹⁵=Me, R⁹⁴-acyl, M═O;

(XIII-Y) R⁸⁶=R⁸⁷=R⁸⁸=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=R⁹³=H, R⁹⁵=

R⁹⁴=COCH₂CH(CH₃)₂, M═O;

(XIII-Z) R⁸⁶=R⁸⁷=R⁸⁸=R⁸⁹=R⁹⁰=R⁹¹=R⁹²=R⁹³H, R⁹⁵=CH₂-φ, R⁹=acyl, M═O;

Non-limiting examples of suksdorfin analogs according to formula (XIV)include the following combinations of R⁹⁷, R⁹⁸, R⁹⁹, R¹⁰⁰, X, Y, Z andM.

(XIV-A) R⁹⁷=R⁹⁸R⁹⁹R¹⁰⁰=H, M═Y═Z═O, X═NH

(XIV-B) R⁹⁷=R⁹⁸=R¹⁰⁰=H, R⁹⁹=alkyl, M═Y═Z═O, Z═NH

(XIV-C) R⁹⁸=R⁹⁹=R¹⁰⁰=H, R⁹⁷=O-alkyl, M═Y═Z═O, Z═NH

(XIV-D) R¹⁴=R¹⁵=R¹⁶=R¹⁷=R¹⁸H, R⁹⁷==O-CH₂CONH-alkyl, M═Y-Z═O, X═NH

(XIV-E) R⁹⁹=R¹⁰⁰=acyl, R⁹⁷=R¹⁴=R¹⁵=R¹⁶=H, M═Y═Z-O, X═NH

(XIV-F) R⁹⁹=R¹⁰⁰=acyl, R⁹⁸=O-alkyl, R⁹⁷=H, M═Y═Z═O, X═NH

(XIV-G) R⁹⁹=R¹⁰⁰=acyl, R⁹⁷=O-alkyl, O-CF₃, O-CH₂CCO-alkyl, R⁹⁸=H,M═Y═Z═O, X═NH

(XIV-H) R⁹⁹=R¹⁰⁰=acyl, R⁹⁸H, R⁹⁷=O-CH₂CONH-alkyl, M═Y═Z═O, X═NH

(XIV-J) R⁹⁹=R¹⁰⁰=acyl, R⁹⁷=halogen or CH₂CH₂N-alkyl, R⁹⁸=alkyl, M═Y═Z═O,X═NH

(XIV-K) R⁹⁷=R⁹⁸=R¹⁰⁰=H, R⁹⁹=alkyl or COCH(CH₃)C₂H₅, M═Y═Z═O, X═NH

(XIV-L) R⁹⁷=R⁹⁸=R⁹⁹=H, R¹⁰⁰=alkyl, or, COCH(CH₃)C₂H₅, M═Y═Z═O, X═NH

(XIV-M) R⁹⁷=R⁹⁸=H, R⁹⁹=R¹⁰⁰=acyl, M═Y═Z═O, X═NH

(XIV-N) R⁹⁷=R⁹⁸=H, R⁹⁹=R¹⁰⁰=COCH(CH₃)C₂H₅, M═Y═Z═O, X═NH

(XIV-O) R⁹⁷=R⁹⁸=H, R⁹⁹=R¹⁰⁰=COCH₂CH(CH₃)₂, M═Y═Z═O, X═NH

(XIV-P) R⁹⁷=R⁹⁸=H, R⁹⁹=R¹⁰⁻=

M═Y═Z═O, Z═NH

(XIV-Q) R⁹⁷=R⁹⁸=H, R⁹⁹=acyl, R¹⁰⁰=COCH(CH₃)C₂H₅, M═Y═Z═O, X═NH

(XIV-R) R⁹⁷=R⁹⁸=H, R¹⁰⁰=COCH(CH₃)C₂H₅, R⁹⁹=acyl, M═Y═Z═O, X═NH

(XIV-S) R⁹⁷=R⁹⁸=R⁹⁹=H, R¹⁰⁰=acyl, M═Y═Z═O, X═NH

(XIV-T) R⁹⁷=R⁹⁸=R⁹⁹=H, R¹⁰⁰=COCH₂CH(CH₃)₂, M═Y═Z═O, X═NH

(XIV-U) R⁹⁷=R⁹⁸=R⁹⁹=H, R¹⁰⁰=CH₂φ, where φ=phenyl, M═Y═Z═O, X═NH

(XIV-V) R⁹⁷=R⁹⁸=R⁹⁹=H, R¹⁰⁰=Me, M═Y═Z═O, X═NH

(XIV-W) R⁹⁷=R⁹⁸=R⁹⁹=H, R¹⁰⁰=

M═Y═Z═O, X═NH

(XIV-X) R⁹⁷=R⁹⁸H, R¹⁰⁰=Me, R⁹=acyl, M═Y═Z═O, X═NH

(XIV-Y) R⁹⁷=R⁹⁸=H, R¹⁰⁰=

R⁹⁹=COCH₂CH(CH₃)₂, M═Y═Z═O, X═NH

(XIV-Z) R⁹⁷=R⁹⁸=H, R¹⁰⁰ =CH₂-φ, R⁹⁹=acyl, MY═Z═O,, X═NH

Non-limiting examples of suksdorfin analogs according to formula (XV)include the following combinations of R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶,R¹⁰⁷, X, Z and M.

(XV-A) R¹⁰²R¹⁰³R¹⁰⁴=R¹⁰⁵=R¹⁰⁶=R¹⁰⁷=H, M═Z═O, X═NH

(XV-B) R¹⁰²=R¹⁰³=R¹⁰⁴=R¹⁰⁵=R¹⁰⁷=H, R¹⁰⁶=alkyl, M═R═O, X═NH

(XV-C) R¹⁰³=R¹⁰⁴=R¹⁰⁵=R¹⁰⁶=R¹⁰⁷=H, R¹⁰²=O-alkyl, M═R═O, X═NH

(XV-D) R¹⁰³=R¹⁰⁴=R¹⁰⁵=R¹⁰⁹⁶=R¹⁰⁷=H, R¹⁰²=O-CHCONH-alkyl, M═Z═O, X═H

(XV-E) R¹⁰⁶=R¹⁰⁷=acyl, R¹⁰²=R¹⁰³=R¹⁰⁴=R¹⁰⁵=H, M═Z═O, X═NH

(XV-F) R¹⁰⁶=R¹⁰⁷=acyl, R¹⁰³=O-alkyl, R¹⁰²=R¹⁰³=R¹⁰⁴=H, M═Z═O, X═NH

(XV-G) R¹⁰⁶=R¹⁰⁷=acyl, R¹⁰²=O-alkyl, O-CF₃, O-CH₂COO-alkyl,R¹⁰³=R¹⁰⁴=R¹⁰⁵=H, M═Z═O, X═NH

(XV-H) R¹⁰⁶=R¹⁰⁷−acyl, R¹⁰³=R¹⁰⁴=R¹⁰⁵=H, R¹⁰²=O-CH₂CONH-alkyl, M═Z═O,X═NH

(XV-J) R¹⁰⁶=R¹⁰⁷=acyl, R¹⁰⁴=R¹⁰⁵=R¹⁰²=halogen or CH₂CH₂N-alkyl,R¹⁰³=alkyl, M═R═O, X═NH

(XV- K) R¹⁰²=R¹⁰³=R¹⁰⁴=R¹⁰⁵=R¹⁰⁷=H, R¹⁰⁶=alkyl or COCH(CH₃)C₂H₅, M═Z═O,X═NH

(XV-L) R¹⁰²=R¹⁰³=R¹⁰⁴=R¹⁰⁵=R¹⁰⁶=H, R¹⁰⁷=alkyl or, COCH(CH₃)C₂H₅, M═Z═O,X═NH

(XV-M) R¹⁰²=R¹⁰³=R¹⁰⁴=R¹⁰⁵=H, R¹⁰⁶=R¹⁰⁷=acyl, M═Z═O, X═NH

(XV-N) R¹⁰²=R¹⁰³=R¹⁰⁴=R¹⁰⁵=H, R¹⁰⁶=R¹⁰⁷=COCH(CH₃)C₂H₅, M═Z═O, X═NH

(XV-O) R¹⁰²=R¹⁰³=R¹⁰⁴=R¹⁰⁵=H, R¹⁰⁶=R¹⁰⁷=COCH₂CH(CH₃)₂, M═Z═O, X═NH

(XV-P) R¹⁰²=R¹⁰³=R¹⁰⁴=R¹⁰⁵=H, R¹⁰⁶=R¹⁰⁷=

M═R═O, X═NH

(XV-Q) R¹⁰²=R¹⁰³=R¹⁰⁴=R¹⁰⁵=H, R¹⁰⁶-acyl, R¹⁰⁷⁼COCH(CH₃)C₂H₅, M═Z═O, X═NH

(XV-R) R¹⁰²=R¹⁰³=R¹⁰⁴=R¹⁰⁵=H, R¹⁰⁷=COC(CH₃)C₂H₅, R¹⁰⁶=acyl, Y═Z═O, X═NH

(XV-S) R¹⁰²=R¹⁰³=R¹⁰⁴=R¹⁰⁵=R¹⁰⁶=H, R¹⁰⁷=acyl, M═R═O, X═NH

(XV-T) R¹⁰²=R¹⁰³=R¹⁰⁴=R¹⁰⁵=R¹⁰⁶=H, R¹⁰⁷-COCH₂CH(CH₃)₂, M═R═O, X═NH

(XV-U) R¹⁰²=R¹⁰³=R¹⁰⁶=R¹⁰⁶=H, R¹⁰⁷=CH₂φ, where φ=phenyl, M═R═O, X═NH

(XV-V) R¹⁰²=R¹⁰³=R¹⁰⁴=R¹⁰⁵=R¹⁰⁶=H R¹⁰⁷=Me, M═R═O, X═NH

(XV-W) R¹⁰²=R¹⁰³=R¹⁰⁴=R¹⁰⁵=R¹⁰⁶=H,

M═Z═O, X═NH

(XV-X) R¹⁰²=R¹⁰³=R¹⁰⁴=R¹⁰⁵−H, R¹⁰⁷=Me, R¹⁰⁶=acyl, M═Z═O, X═NH

(XV-Y) R¹⁰²=R¹⁰³=R¹⁰⁴=R¹⁰⁵=H, R¹⁰⁷=

R¹⁰⁶=COCH₂CH(CH₃)₂, M═Z═O, X═NH

(XV-Z) R¹⁰²=R¹⁰³=R¹⁰⁴=R¹⁰⁵=H, $¹⁰⁷=CH₂-φ, R¹⁰⁶=acyl, M═Z═O, X═NH

Non-limiting examples of suksdorfin analogs according to formula (XVI)include the following combinations of R¹⁰⁹, R¹¹⁰, R¹¹¹, R¹¹², R¹¹³,R¹¹⁴, X, Y, Z, and M.

(XVI-A) R¹⁰⁹=R¹¹⁰=R¹¹¹=R¹¹²=R¹¹³=R¹¹⁴=H, M═Y═Z═O, X═NH

(XVI-B) R¹⁰⁹=R¹¹⁰=R¹¹¹=R¹¹²=R¹¹⁴=H, R¹¹³=alkyl, M═Y═Z═O, X═NH

(XVI-C) R¹¹⁰=R¹¹¹=R¹¹²=R¹¹³=R¹¹⁴=H, R¹⁰⁹=O-alkyl, M═Y═Z═O, X═NH

(XVI-D) R¹¹⁰=R¹¹¹=R¹¹²=R¹¹³=R¹¹⁴=H, R¹⁰⁹O-CH₂CONH-alkyl, M═Y═Z═O, X═NH

(XVI-E) R¹¹³=R¹¹⁴=acyl, R¹⁰⁹=R¹¹⁰=R¹¹¹=R¹¹²=H, M═Y═Z═O, X═NH

(XVI-F) R¹¹³=R¹¹⁴=acyl, R¹¹²=O-alkyl, R¹⁰⁹=R¹¹⁰=R¹¹¹=H, M═Y═Z═O, X═NH

(XVI-G) R¹¹³=R¹¹⁴=acyl, R¹⁰⁹=O-alkyl, O-CF₃, O-CH₂COO-alkyl,R¹¹⁰=R¹¹¹=R¹¹²-H, M═Y═Z═O, X═NH

(XVI-H) R¹¹³=R¹¹⁴=acyl, R¹¹⁰=R¹¹¹=R¹¹²=H; R¹⁰⁹=O-CH₂CONH-alkyl, M═Y═Z═O,X═NH

(XVI-J)R¹¹³=R¹¹⁴=acyl, R¹¹¹=R¹¹²=H, R¹⁰⁹=halogen or CH₂CHN-alkyl,R¹¹⁰=alkyl, M═Y═Z═O, X═NH

(XVI-K) R¹⁰⁹=R¹⁰¹=R¹¹¹=R¹¹²=R¹¹⁴=H, R¹¹³=alkyl or COCH (CH₃)C₂H₅,M═Y═Z═O, X═NH

(XVI-L) R¹⁰⁹=R¹¹⁰=R¹¹¹=R¹¹²=R¹¹³=H, R¹¹⁴=alkyl or, COCH (CH₃)C₂H₅,M═Y═Z═O, X═NH

(XVI-M) R¹⁰⁹=R¹¹⁰=R¹¹¹=R¹¹²=H, R¹¹³=R¹¹⁴=acyl, ═Y═Z═O, X═NH

(XVI-N) R¹⁰⁹=R¹¹⁰=R¹¹¹=R¹¹²=H, R¹¹³=R¹¹⁴=COCH(CH₃)C₂H₅, M═Y═Z═O, X═NH

(XVI-O) R¹⁰⁹=R¹¹⁰=R¹¹¹=R¹¹²=H, R¹¹³=R¹¹⁴=COCH.2CH (CH₃)₂, M═Y═Z=, X═NH

(XVI-P) R¹⁰⁹=R¹¹⁰=R¹¹¹=R¹¹²=H, R¹¹³=R¹¹⁴=

M═Y═Z═O, X═NH

(XVI-Q) R¹⁰⁹=R¹¹⁰=R¹¹¹=R¹¹²=H, R¹¹³=acyl, R¹¹⁴=COCH(CH₃)C₂H₅, M═Y═Z═O,X═NH

(XVI-R) R¹⁰⁹ ⁰=R¹¹⁰=R¹¹¹=R¹¹²=H, R¹¹⁴=COCH(CH₃)C₂H₅, R¹¹³=acyl, M═Y═Z═O,X═NH

(XVI-S) R¹⁰⁹=R¹¹⁰=R¹¹¹=R¹¹²=R¹¹³=H, R¹¹⁴=acyl, M═Y═Z═O, X═NH

(XVI-T) R¹⁰⁹=R¹¹⁹=R¹¹¹=R¹¹²=R¹¹³=H, R¹¹⁴=COCH₂CH(CH₃)₂ M═Y═Z═O, X═NH

(XVI-U) R¹⁰⁹=R¹¹⁰=R¹¹¹=R¹¹²=R¹¹³=H, R¹¹⁴=CH₂φ, where φ=phenyl, M═Y═Z═O,X═NH

(XVI-V) R¹⁰⁹=R¹¹⁰=R¹¹¹=R¹¹²=R¹¹³=H, R¹¹⁴=Me, M═Y═Z═O, X═NH

(XVI-W) R¹⁰⁹R¹¹⁰=R¹¹²=R¹¹³=H, R¹¹⁴=

M═Y═Z═O, X≡NH

(XVI-X) R¹⁰⁹=R¹¹⁰=R¹¹¹=H, R¹¹⁴=Me, R¹¹³=acyl, M-Y-Z═O, X═NH

(XVI-Y) R¹⁰⁹=R¹¹⁰=R¹¹¹=R¹¹²=H, R¹¹⁴=

R¹¹³=COCH₂CH(CH₃)₂, M═Y═Z═O, X═NH

(XVI-Z) R¹⁰⁹=R¹¹⁰=R¹¹¹=R¹¹²=H, R¹¹⁴=CH₂-φ, R¹¹³=acyl, M═Y═Z═O,, X═NH

Non-limiting examples of suksdorfin analogs according to formula (XVII)include the following combinations of R¹¹⁶, R¹¹⁷, R¹¹³ R¹¹⁹, R¹²⁰, R¹²¹,R¹²², R¹²³, X, Y, Z and M.

(XVII-A) R¹¹⁶=R¹¹⁷=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=R¹²²=R¹²³=H, M═Y═Z═O, X═NH

(XVII-B) R¹¹⁶=R¹¹⁷=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=R¹²³=H, R¹²²=alkyl, M═Y═Z═O, X═NH

(XVII-C) R¹¹⁶=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=R¹²²=R¹²³=H, R¹¹⁷=-O-alkyl, M═Y═Z═O,X═NH

(XVII-D) R¹¹⁶=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=R¹²²=R¹²³=H, R¹¹⁷=O-CH₂CONH-alkyl,M═Y═Z═O, X═NH

(XVII-E) R¹²²=R¹²³=acyl, R¹¹⁶=R¹¹⁷=R¹¹⁹=R¹²⁰=R¹²¹=H, M═Y═Z═O, X═NH

(XVII-F) R¹²²=R¹²³=acyl, R¹²¹=O-alkyl, R¹¹⁶=R¹¹⁷=R¹¹⁸=R¹¹⁹=R¹²⁰=H,M═Y═Z═O, X═NH

(XVII-G) R¹²²=R¹²³=acyl, R¹¹⁷=O-alkyl, O-CF₃, O-CH₂COO-alkyl,R¹¹⁶=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=H, M═Y═Z═O, X═NH

(XVI-H) R¹²²=R¹²³=acyl, R¹¹⁶=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=H,R¹¹⁷=O-CH₂CONH-alkyl, M═Y═Z═O, X═NH

(XVII-J) R¹²²=R¹²³-acyl, R¹¹⁶=R¹¹⁸=R¹²⁰=R¹²¹=H, R¹¹⁷=halogen orCH₂CH₂N-alkyl, R¹¹⁹=alkyl, X═Y═Z═O, X═NH

(XVII-K) R¹¹⁶=R¹¹⁷=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=R¹²³=H, R¹²²=alkyl orCOCH(CH₃)C₂H₅, M═Y═Z═O, X═NH

(XVII-L) R¹¹⁶=R¹¹⁷=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=R¹²²=H, R¹²³-alkyl or,COCH(CH₃)C₂H₅, M═Y═Z═O, X═NH

(XVII-M) R¹¹⁶=R¹¹⁷=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=H, R¹²²=R¹²³=acyl, M═Y═Z═O, X═NH

(XVII-N) R¹¹⁶=R¹¹⁷=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=H, R¹²²=R¹²³=COCH(CH₃(C₂H₅,M═Y═Z═O X═NH

(XVII-O) R¹¹⁶=R¹¹⁷=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=H, R¹²²=R¹²³=COCH₂CH(CH₃)₂,M═Y═Z═O, X═NH

(XVII-P) R¹¹⁶=R¹¹⁷=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=H, R¹²²=R¹²³=

M═Y═Z═O, X═NH

(XVII-Q) R¹¹⁶=R¹¹⁷=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=H, R¹²²=acyl R¹²³=COCH(CH₃)C₂H₃,M═Y═Z═O, X═NH

(XVII-R) R¹¹⁶=R¹¹⁷=R¹⁸¹R=R¹¹⁹=R¹²⁰=R¹²¹=H, R¹²³=COCH(CH₃)C₂H₅,R¹²²=acyl, M═Y═Z═O, X═NH

(XVII-S) R¹¹⁶=R¹¹⁷=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=R¹²²=H, R¹²³=acyl, M═Y═Z═O, X═NH

(XVII-T) R¹¹⁶=R¹¹⁷=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=R¹²²=H, R¹²³=COCH₂CH (CH₃)₂,M═Y═Z═O, X═NH

(XVII-U) R¹¹⁶=R¹¹⁷=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=R¹²²=H, R¹²³=CH₂φ, whereφ=phenyl, M═Y═Z═O, X═NH

(XVII-V) R¹¹⁶=R¹¹⁷=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=R¹²²=H, R¹²³=Me, M═Y═Z═O, X═NH

(XVII-W) R¹¹⁶=R¹¹⁷=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=R¹²²=H, R¹²³=

M═Y═Z═O, X═NH

(XVII-X) R¹¹⁶=R¹¹⁷=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=H, R¹²² acyl, M═Y Z═O,

(XVII-Y) R¹¹⁶=R¹¹⁷=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=H, R¹²³=

R¹²²COCH₂CH(CH₃)₂, M═Y═Z═O, X═NH

(XVII-Z) R¹¹⁶=R¹¹⁷=R¹¹⁸=R¹¹⁹=R¹²⁰=R¹²¹=H, R¹²³=CH₂-φ, R¹²²=acyl,M═Y═Z═O, X═NH

Non-limiting examples of suksdorf in analogs according to formula(XVIII) include the following combinations of R¹²⁵ , R¹²⁶, R¹²⁷, R¹²⁸,R¹²⁹, R¹³⁰, R¹³¹, X, Z, Z and M.

(XVIII-A) R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸=R¹²⁹=R¹³⁰=R¹³¹=H, M═Y═Z═O, Z═NH

(XVIII-B) R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸=R¹²⁹=R¹³¹=H, R¹³⁰=alkyl, M═Y═Z═O, X═NH

(XVIII-C) R¹²⁵=R¹²⁶=R¹²⁸=R¹²⁹=R¹³⁰=R¹³¹=H, R¹²⁷=O-alkyl, M═Y═Z═O, X═NH

(XVIII-D) R¹²⁵=R¹²⁶=R¹²⁸=R¹²⁹=R¹³⁰=R¹³¹=H, R¹²⁷=O--CH₂CONH-alkyl,M═Y═Z═O, X═NH

(XVIII-E) R¹³⁰=R¹³¹=acyl, R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸=R¹²⁹=H, M═Y═Z═O, X═NH

(XVIII-F) R¹³⁰=R¹³¹=acyl, R¹²⁹-O-alkyl, R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸=H, M═Y═Z═O,X═NH

(XVIII-G) R¹³⁰=R¹³¹=acyl, R¹²⁷-O-alkyl, O-CF₃, O-CH₂COO-alkyl,R¹²³=R¹²⁶=R¹²⁸=R¹²⁹=H, M═Y═Z═O, X═NH

(XVIII-H) R¹³⁰=R¹³¹=acyl, R¹²⁵=R¹²⁶=R¹²⁸=R¹²⁹=H, R¹²⁷=O-CH₂CONH -alkyl,M═Y═Z═O, X═NH

(XVIII-J) R¹³⁰=R¹³¹=acyl, R¹²⁵=R¹⁵=R¹⁶=H, R¹²⁷=halogen or CH₂CH₂N-alkyl,R¹²⁸=alkyl, M═YZ═O, X═NH

(XVIII-K) R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸=R¹²⁹=R¹³¹=H, R¹³⁰=alkyl or COCH (CH₃)C₂H₅, M-Y═Z═O, X═NH

(XVIII-L) R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸=R¹²⁹=R¹³⁰=H, R¹³¹=alkyl or, COCH(CH₃)C₂H₅, M═Y═Z═O, X═NH

(XVIII-M) R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸=R¹²⁹=H, R¹³⁰=R¹³¹=acyl, M═Y═Z═O, X═NH

(XVIII-N) R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸=R¹²⁹=H, R¹³⁰=R¹³¹=COCH(CH₃)C₂H₅, M═Y═Z═O,X═NH

(XVIII-O) R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸=R¹²⁹=H, R¹³⁰=R¹³¹=COCH₂CH(CH₃)₂, M═Y═Z═O,X═NH

(XVIII-P) R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸=R¹²⁹=H, R¹³⁰=R¹³¹=

M═Y═Z═O, X═NH

(XVIII-Q) R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸=R¹²⁹=H, R¹³⁰-acyl, R¹³¹=COCH(CH₃)C₂H₅,M═Y═Z═O, X═NH

(XVIII-R) R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸=R¹³⁹=H, R¹³¹=COCH(CH₃)C₂H₅, R¹³⁰=acylM═Y═Z═O, X═NH

(XVIII-S) R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸=R¹²⁹=R¹³⁰=H, R¹³¹acyl, M═Y═Z═O, X═NH

(XVIII-T) R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸=R¹²⁹=R¹³⁰=H, R¹³¹=COCH₂CH(CH₃)₂, M═Y═Z═O,

X═NH

(XVIII-U) R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸=R¹²⁹=R¹³⁰=H, R¹³¹=CH₂φ, where φ-phenyl,M═Y═Z═O, X═NH

(XVIII-V) R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸=R¹²⁹=R¹³⁰=H, R¹³¹=Me, M═Y═Z═O, X═NH

(XVIII-W) R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸R¹²⁹R¹³⁰=H, R¹³¹=

M═Y═Z═O, X═NH

(XVIII-X) R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸=R¹²⁹=H, R¹³¹=Me, R¹³⁰=acyl, M══Z═O, X═NH

(XVIII-Y) R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸=R¹³⁰=H, R¹³¹=

R¹³⁰=COCH₂CH(CH₃)₂, M═Y═Z═O, X═NH

(XVIII-Z) R¹²⁵=R¹²⁶=R¹²⁷=R¹²⁸=R¹²⁹=H, R¹³¹=CH₂-10 , R¹³⁰-acyl, M═Y═Z═O,X═NH

Non-limiting examples of suksdorfin analogs according to formula (XIX)include the following combinations of R¹³³, R¹³⁴, R¹³⁵, R¹³⁶. R¹³⁷,R¹³⁸, R¹³⁹, R¹⁴⁰, Z and M.

(XIX-A) R¹³³=R¹³⁴=R¹³⁵=R¹³⁶=R¹³⁷=R¹³⁸=R¹³⁹=R¹⁴⁰=H, M═R═O, X═NH

(XIX-B) R¹³³=R¹³÷R¹³⁵=R¹³⁶=R¹³⁷=R¹³⁸=R¹⁴⁰=H, R¹³⁹=alkyl, M═Y═Z═O, X═NH

(XIX-C) R¹³³=R¹³⁴=R¹³⁶=R¹³⁷=R¹³⁶=R¹³⁹=R¹⁴⁰=H, R¹³⁵=O -alkyl, M═R═O;

(XIX-D) R¹³³=R¹³⁴=R¹³⁶=R¹³⁷=R¹³⁸=R¹³⁹=R¹⁴⁰=H, R¹³⁵=O-CH₂CONH-alkyl,M═R═O, X═NH

(XIX-E) R¹³⁹=R¹⁴⁰-acyl, R¹³³=R¹³⁴=R¹³⁵=R¹³⁶=R¹³⁷=R¹³³=H, M═R═O;

(XIX-F) R¹³⁹=R¹⁴⁰=acyl, R¹³⁸=O-alkyl, R¹³³=R¹³=R¹³⁵=R¹³⁷=H, M═Z═O,

(XIX-G) R¹³⁷=R¹⁴⁰=acyl, R¹³⁵=O-alkyl, O-CF₃, O-CH₂COO-alkyl,R¹³³=R¹³⁴=R¹³⁶=R¹³⁷=R¹³⁸=H, M═Z═O;

(XIX-H) R¹³⁹=R¹⁴⁰=acyl, R¹³³=R¹³⁴=R¹³⁶=R¹³⁷=R¹³⁸=H, R¹³⁵=O-CH₂CONH-alkyl, M═R═O;

(XIX-J) R¹³⁹=R¹⁴⁰=acyl, R¹³³=R¹³⁴=R¹³⁷=R¹³⁸=H, R¹³⁵=halogen orCH₂CN-alkyl, R¹³⁶=alkyl, M═R═O;

(XIX-K) R¹³³=R¹³⁴=R¹³⁵=R¹³⁶=R¹³⁷=R¹³⁸=R¹⁴⁰=H, R¹³⁹=alkyl or COCH(CH₃)C₂H₅, M═Z═O;

(XIX-L) R¹³³=R¹³⁴=R¹³⁵=R¹³⁶=R¹³⁷=R¹³⁸=R¹³⁹=H, R¹⁴⁰=alkyl or, COCH(CH₃)C₂H₅, M═Z═O;

(XIX-M) R¹³³=R¹³⁴=R¹³⁵=R¹³⁶=R¹³⁷=R¹³⁸=H, R¹³⁹=R¹⁴⁰=acyl, M═Z═O;

(XIX-N) R¹³³=R¹³⁴=R¹³⁵=R¹³⁶=R¹³⁷=R¹³⁸=H, R¹³⁹=R¹⁴COCH (CH₃)C₂H₅, M═R═O;

(XIX-O) R¹³³=R¹³⁴=R¹³⁵=R¹³⁶=R¹³⁷=R¹³⁸=H, R¹³⁹=R¹⁴⁰COCH(CH₃)₂, M═Z═O;

(XIX-P) R¹³³=R¹³⁴=R¹³⁵=R¹³⁶=R¹³⁷=R¹³⁸=H, R¹³⁹=R¹⁴⁰=

M═R═O ;

(XIX-Q) R¹³³=R¹³⁴=R¹³⁵=R¹³⁶=R¹³⁷=R¹³⁸=H, R¹³⁹=acyl, R¹⁴⁰=COCH(CH₃)C₂H₅,M═R═O;

(XIX-R) R¹³³=R¹³⁴=R¹³⁵=R¹³⁶R¹³⁷=R¹³⁸=H, R¹⁴⁰=COCH(CH₃)C₂H₅, R¹³⁹=acyl,M═Z═O;

(XIX-S) R¹³³=R¹³⁴=R¹³⁵=R¹³⁶=R¹³⁷=R¹³⁸=R¹³⁹=H, R¹⁴⁰=acyl, M═Z═O;

(XIX-T) R¹³³=R¹³⁴=R¹³⁵=R¹³⁶=R¹³⁷=R¹³⁸=R¹³⁹=H, R¹⁴⁰COCH₂CH (CH₃)₂, M═R═O;

(XIX-U) R¹³³=R¹³⁴=R¹³⁵=R¹³⁶=R¹³⁷R¹³⁸=R¹³⁹=H, R¹⁴⁰=CH₂φ, where φ=phenyl,M═Z═O;

(XIX-V) R¹³³=R¹³⁴=R¹³⁵=R¹³⁶=R¹³⁷=R¹³⁸=R¹³⁹=H, R¹⁴⁰=Me M═R═O;

(XIX-W) R¹³³=R¹³⁴=R¹³⁵=R¹³⁶=R¹³⁷=R¹³⁸=R¹³⁹=H, R¹⁴⁰=

M-Z═O;

(XIX-X) R¹³³=R¹³⁴=R¹³⁵=R¹³⁶=R¹³⁷=R¹³⁸=H, R¹⁴⁰=Me, R¹³⁹=acyl, M═Z═O;

(XIX-Y) R¹³³=R¹³⁴=R¹³⁵=R¹³⁶=R¹³⁷=R¹³⁸=H, R¹⁴⁰=

R¹³⁹=COCH₂CH(CH₃)₂, M═R═O;

(XIX Z) R¹³³=R¹³⁴=R¹³⁵=R¹³⁶=R¹³⁷=R¹³⁸=H, R¹⁴⁰=CH₂-φ, R¹³⁹=acyl, M═R═O;

Non-limiting examples of suksdorf in analogs according to formula (XX)include the following combinations of R¹⁴², R¹⁴³, R¹⁴⁴, R¹⁴⁵, R¹⁴⁶, Zand M.

(XX-A) R¹⁴²=R¹⁴³=R¹⁴⁴=R¹⁴⁵=R¹⁴⁶=H, M═Z═O;

(XX-B) R¹⁴²=R¹⁴³=R¹⁴⁴=R¹⁴⁶=H, R¹⁴⁵=alkyl, M═Z═O;

(XX-C) R¹⁴³=R¹⁴⁴=R¹⁴⁵=R¹⁴⁶=H, R¹⁴²=O-alkyl, M═R═O;

(XX-D) R¹⁴³=R¹⁴⁴=R¹⁴⁵=R¹⁴⁵=H, R¹⁴²=O-CH₂CONH-alkyl, M═R═O; (XX-E)R¹⁴⁵=R¹⁴⁶=acyl, R¹⁴²=R¹⁴³=R¹⁴⁴=H, M═R═O;

(XX-F) R¹⁴⁵=R¹⁴⁶=acyl, R¹⁴⁶=O-alkyl, R¹⁴²=R¹⁴³=H, M═R═O;

(XX-G) R¹⁴⁵=R¹⁴⁶=acyl, R¹⁴²=O-alkyl, O-CF₃, O-CH₂COO-alkyl, R¹⁴³=R¹⁴⁴=H,M═Z═O;

(XX-H) R¹⁴⁵=R¹⁴⁶=acyl, R¹⁴³=R¹⁴⁴=H, R¹⁴²O-CH₂CONH-alkyl, M═Z═O;

(XX-G) R¹⁴⁵=R¹⁴⁶=acyl, R¹⁴⁴=H, R¹⁴²=halogen or CH₂CH₂N-alkyl,R¹⁴³=alkyl, M═R═O;

(XX-K) R¹⁴²=R¹⁴⁴=R¹⁴⁶=H, R¹⁴⁵=alkyl or COCH(CH₃)C₂H₅, M═Z═O;

(XX-L) R¹⁴²=R¹⁴³=R¹⁴⁴=R¹⁴⁵=H, R¹⁴⁶=alkyl or, COCH(CH₃)C₂H₅, M═Z═O;

(XX-M) R¹⁴²=R¹⁴³=R¹⁴⁴=H, R¹⁴⁵=R¹⁴⁶=acyl, M═Z═O;

(XX-N) R¹⁴²=R¹⁴³=R¹⁴⁴=H, R¹⁴⁵=R¹⁴⁶=COCH (CH₃)C₂H₅, M═Z═O;

(XX-O) R¹⁴²=R¹⁴³=R¹⁴⁴=H, R¹⁴⁵=R¹⁴⁶=COCH₂CH (CH₃)₂, M═Z═O;

(XX-P) R¹⁴²=R¹⁴³=R¹⁴⁴=H, R¹⁴⁵=R¹⁴⁶=

M═Z═O

(XX-Q) R¹⁴²=R¹⁴³=R¹⁴⁴=H, R¹⁴⁵=acyl, R¹⁴⁶=COCH(CH₃)C₂H₅, M═Z═O;

(XX-R) R¹⁴²=R¹⁴³=R¹⁴⁴=H, R¹⁴⁶=COCH(CH₃)C₂H₅, R¹⁴⁵=acyl, M═Z═O;

(XX-S) R¹⁴²=R¹⁴³=R¹⁴⁴=R¹⁴⁵=H, R¹⁴⁶=acyl, M═Z═O;

(XX-T) R¹⁴²=R¹⁴³=R¹⁴⁴=R¹⁴⁵H, R¹⁴⁶=COCH₂CH(CH₃)₂, M═R═O;

(XX-U) R¹⁴²=R¹⁴³=R¹⁴⁴=R¹⁴⁵=H, R¹⁴⁶=CH₂φ, where φ=phenyl, M═Z═O;

(XX-V) R¹⁴²=R¹⁴³=R¹⁴⁴=R¹⁴⁵=H, R¹⁴⁶=Me, M═R═O;

(XX-W) R¹⁴²=R¹⁴³=R¹⁴⁴=R¹⁴⁵=H, R¹⁴⁶=

M═Z═O;

(XX-X) R¹⁴²=R¹⁴³=R¹⁴⁴=H, R¹⁴⁶=Me, R¹⁴⁵acyl, M═R═O;

(XX-Y) R¹⁴²=R¹⁴³=R¹⁴⁴=H, R¹⁴⁶=

R¹⁴⁵=COCH₂CH(CH₃)₂, M═R═O;

(XX-Z) R¹⁴²=R¹⁴³=R¹⁴⁴=H, R¹⁴⁶-CH₂-φ, R¹⁴⁵=acyl, M═R═O;

Such suksdorf in analogs have been unexpectedly discovered to haveanti-retroviral activity, thus providing suitable compounds andcompositions for treating retroviral infections, optionally withadditional pharmaceutically active ingredients, such as anti-retroviral,anti-HIV, and/or immuno-stimulating compounds or antiviral antibodies orfragments thereof.

By the term “anti-retroviral activity” or “anti-HIV activity” isintended the ability to inhibit at least one of (1) retroviralattachment to cells, (2) viral entry into cells, (3) cellular metabolismwhich permits viral replication, (4) inhibition of intercellular spreadof the virus, (5) synthesis and/or cellular expression of viralantigens, (6) activity of virus-coded enzymes (such as reversetranscriptase and protease), and/or (7) any known retroviral or HIVpathogenic actions, such as, for example, immunosuppression. Thus, anyactivity which tends to inhibit any of these mechanisms is“anti-retroviral activity” or “anti-HIV activity.”

The present invention also provides a process for purifying suksdorfinanalogs having anti-HIV activity from a sample containing such acompound, such as, but not limited to, the fruit of the plant Lomatiumsuksdorfi, the method comprising: (a) extracting sample preparationswith hexane to provide active fractions; (b) centrifuging the activefractions at least once; (c) recovering the supernatant; and (d)purifying the precipitate by silica gel chromatography to recover thesuksdorfin analog, thereby purifying the protein.

The present invention also provides alternative synthetic methods forobtaining suksdorfin analogs according to formula (I) or formula (II).

The following scheme 1 provides one set of alternative synthetic stepsfor producing compounds synthesis of suksdorf in analogs according toformula (I), based on a synthesis of seselin (2) from 7-hydroxy coumarin1.

The construction of the pyran ring from commercially available7-hydroxycoumarin (1) involved two steps (1 and 2), which have beendescribed, e.g. by Hlubucek, et al. Aust. J. Chem. 24:2347 (1971) thecontents of which is incorporated entirely herein by reference. Thecrude product of the first step can be used directly in the nextrearrangement reaction, which will produce seselin (2) in good yield.Seselin can then be used as the starting material for the synthesis ofother pyranocoumarin derivatives as presented in Scheme 1, as furtherdescribed herein, using at least one intermediate compounds designatedcompounds 3-7, to produce suksdorf in analogs of the present invention,non-limiting as examples of compounds according to formula (I), e.g., asanalogs designated compounds 8-11 in scheme 1 and 3; 4′-di-O-acyl cis -khellactone

TABLE 1 Enaniometric Excesses (ee %) of Seselin 5 from CatalyticAsymmetric Dihydroxylation with Various DHQD-R and DHQ-R ligands entryLigand^(e) T (° C.) time (day) ee %^(a) config.^(b) t.r. %^(c) 1DHQD-CLB 0 4 30 S,S 75 2 DHQD-PHN r.t. 1 61 S,S 75 3 DHQD-PHN 0 4 67 S,S75 4 (DHQD)₂-PYR 0 1 80 S,S 60 5 DHQ-PHN r.t. 1 15 R,R 75 6 DHQ-PHN 0 459 R,R 75 7 DHQ-CLB r.t. 1 15 R,R 75 8 DHQ-CLB 0 4 50 R,R 75 9 DHQ-MEQr.t. 2 34 R,R 81 10 DHQ-MEQ 0 1 50 R,R 62 11 (DHQ)₂-PYR 0 1 86 R,R 58 12(DHQ)₂-PYR 0 2.5 86 R,R  85^(d) ^(a)Enantiomeric excesses weredetermined by ¹HNMR analysis of the bis-(-)camphanic esters, 1 and 2.^(b)The absolute configurations of the diols were determined byliterature comparison.^([1]) ^(c)The turnover rates were calculated fromthe recovered olefin 5. ^(d)Methanesulfonamide was added in thisreaction. ^(e)The ligands are available from Aldrich.

It was found that reaction temperature is also an important factor inthe reaction rate and enantioselectivity. The asymmetric dihydroxylationof seselin requires up to four days to reach a turnover rate of 75% at0° C. If the reaction temperature is raised to room temperature, withoutother changes in the conditions, the reaction rate is faster andreaction time may be shortened to one day. Unfortunately, with increasedtemperature the enantioselectivity of the reaction may also drop (cf.entries 2&3, 5&6, 7&8, and 9&10). When a catalyst, such asmethanesulfonamide, is added, the turnover rate of seselin attemperatures from about −10° C. to about 10° C. is improved, as shown byentry 12. derivatives designated 12-21 in scheme 1.

and 4.4 mg, 2 mmol 2,5-diphenyl-4,6-bis(9-O-dihydroquinyl)pyrimidine in5 mL of aqueous t-butyl alcohol (1:1 by volume) at 0° C. The reactionprogress was monitored by TLC for four days, at which time the turnoverrate of asymmetric dihydroxylation was approximately 75%. Then, one gramof Na₂S₂O₅ was slowly added and the suspension was warmed to roomtemperature for one half hour. The mixture was extracted with CH₂Cl₂ andthe combined organic layers were dried over MgSO₄ and concentrated. Thecrude cis-diol product, compound 6B, was dried in vacuo and was directlyesterified with (−)-(S)-camphanoyl chloride compound 7B, in pyridine atroom temperature for 24 hours without further purification. The yield ofthe mixture of cis-dicamphanoyl khellactones, compounds 1B and 2B, was68%, calculated from seselin. Compound 1B was the predominantenantiomer, and the extent of enantiomeric excess (ee%) was 86%.

Several different chiral ligands were used in catalytic asymmetricdihydroxylation of seselin in order to obtain optimalenantioselectivity. The results are summarized in Table 1. Differentligands result in different major sic enantiomers and 33% values underthe same conditions of asymmetric dihydroxylation. The DHQD-R typeligands produced primarily the alpha,alpha-cis-diol with S,Sconfiguration (entries 1-4). In contrast, DHQ-R type ligands gavebeta,beta-diol, with R,R configuration as the main product (entries5-12). Different R groups in ligands of the same type can result indifferent ee% values, as shown by entries 1 and 3. Among the ligandsused, (DHQD)₂-PYR gave the highest stereoselectivity (entries 4, 11,12).

TABLE 1 Enantiometric Excesses (ee %) of Seselin 5 from CatalyticAsymmetric Dihydroxylaton with Various DHQD-R and DHQ-R ligands entryLigand^(e) T (° C.) time (day) ee %^(a) config.^(b) t.r. %^(c) 1DHQD-CLB 0 4 30 S,S 75 2 DHQD-PHN r.t. 1 61 S,S 75 3 DHQD-PHN 0 4 67 S,S75 4 (DHQD)₂-PYR 0 1 80 S,S 60 5 DHQ-PHN r.t. 1 15 R,R 75 6 DHQ-PHN 0 459 R.R 75 7 DHQ-CLB r.t. 1 15 R,R 75 8 DHQ-CLB 0 4 50 R,R 75 9 DHQ-MEQr.t. 2 34 R,R 81 10 DHQ-MEQ 0 1 50 R,R 62 11 (DHQ)₂-PYR 0 1 86 R,R 58 12(DHQ)₂-PYR 0 2.5 86 R,R  85^(d) ^(a)Enantiomeric excesses weredetermined by ¹HNMR analysis of the bis-(-)-camphanic esters, 1 and 2.^(b)The absolute configurations of the diols were determined byliterature comparison.^([1]) ^(c)The turnover rates were calculated fromthe recovered olefin 5. ^(d)Methanesulfonamide was added in thisreaction. ^(e)The ligands are available from Aldrich.

It was found that reaction temperature is also an important factor inthe reaction rate and enantioselectivity. The asymmetric dihydroxylationof seselin requires up to four days to reach a turnover rate of 75% at0° C. If the reaction temperature is raised to room temperature, withoutother changes in the conditions, the reaction rate is faster andreaction time may be shortened to one day. Unfortunately, with increasedtemperature the enantioselectivity of the reaction may also drop (cf.entries 2&3, 5&6, 7&8, and 9&10). When a catalyst, such asmethanesulfonamide, is added, the turnover rate of seselin attemperatures from about −10° C. to about 10° C. is improved, as shown byentry 12.

The 3′,4′-di-O-acyl- cis-khellactone derivatives (12-21) can be preparedby other routes e.g., as presented in scheme 1. In another route,seselin (2) can be functionalized at the 3′,4′positions by oxidationwith m-chloroperoxybenzoic acid to give the (±)-3′-hydroxy-4′-O-acylderivative 3 (Schroeder et al, Chem. Ber. 92, 2388, (1959), entirelyincorporated herein by reference). Tosic acid catalyzed dehydrationtransformed compound 3 to an optically inactive 3-keto derivativecompound 4 (Willette et al J. Pharm. Sci. 51, 149 1962), entirelyincorporated by reference). According to a disclosed method of procedure(e.g., as presented S. N. Shanbhag et al Tetrahedron, 21:3591 (1965),entirely incorporated herein by reference), treatment of compound 4 withlead tetraacetate in acetic acid can yield the racemic 5. Aftersaponification and reesterification at C-4′ to give a 3′-keto-4′-O-acylintermediate compound 6, the ketone can be reduced to an hydroxyl groupwith NaBH₄ (Shanbhag, supra). Further esterification of this (±)-monoester khellactone with RCOCl or (RCO)₂O can furnish the desired(±)-di-O-acyl-khellactone derivatives followed by carefulchromatographic separation of their cis racemic mixture to providecompounds 8-21 as presented in scheme 1, or other compounds according toFormula I of the present invention.

In yet another route, e.g., as presented in Scheme 1, seselin compound 2can be oxidized with OsO₄ to give the cis-khellactone intermediatecompound 7 in good yield (Schroeder et al, supra). The3′,4′-diester-cis-khellactone compounds 12-17, in which the two estergroups at 3′ and 4′ are identical, can be produced using standardesterification conditions. However, by using equal molar reagents andmild reaction conditions, selective esterification can be achievedgiving the 3′-mono compounds 8 and 9 and the 4′-mono ester khellacetonecompounds 10 and 11 in a mixture with the diesters. Separation andfurther esterification of these mono ester compounds 8-11, using aceticanhydride, can yield the desired (±)-3′,4′-di-O-acyl- cis-khellactonederivative compounds 18-21, which have different ester moieties at the3′ and 4′ positions. This method can have fewer steps and can givebetter yields than route 1, through compound 4. However, route 2 can bemore expensive and require more extensive safety precautions.

Suksdorf in analogs according to formula (I) of the present inventioncan be synthesized as jatamansinol derivatives according to Scheme 3,e.g., using published method steps (e.g., Murry et al Tetrahedronletters, entirely incorporated herein by reference 27:4901 (1971)). Forexample, a phenyl group can be introduced at C-8 of 7-hydroxycoumarincompound 1 in a three-step sequence, which involves a Claisenrearrangement. Under slightly acidic conditions, cyclization ofintermediate compound 23 can furnish jatamansinol compound 24. Usingstandard esterification conditions, (±)-3′-O-acyl-jatamansinolderivative compounds 25 and/or 26 can be synthesized in recoverableamounts.

(±)-3′,4′-Di-O-acyl-trans-khellactone derivatives and3′-O-alkyl-4′-O-acyl-trans-khellactone derivative compounds according toformula (I) can be prepared according to Scheme 3.

Preparation of the 3′,4′-trans derivatives proceeds from intermediatecompound 3A. Compound 3A can be esterified by treatment with theappropriate acyl chloride or acid anhydride to produce the3′,4′-di-O-acyl-trans-khellactone compounds 27,28,33, and 34. Reactionof compound 3A with various alkylating reagents (e.g., MeI, benzylbromide, dihydropyran) can give the 3′-O-alkyl intermediate compounds29-32*. Saponification of these compounds can yield the3′-O-alkyl-4′-hydroxy derivative compounds 35-38. After esterificationwith an acyl chloride or acid anhydride, the(±)-3′-O-alkyl-4′-O-acyl-trans-khellactone derivatives 39-42 can besynthesized, as presented in scheme 4.

Alternatively (±)-Benzodihydropyran derivatives according to formula(II) can be synthesized according to Scheme 3. The lactone ring incompound 3A or in the 3′,4′-di-O-acyl-trans derivatives can be abolishedby using a known hydrolysis method step(s) to give (±)-benzodihydropyran compound 43 according to formula (II). The base (KOH,Ag₂O, or NaH) cleaves the lactone ring and the ester groups. The freeacid or the hydroxyl groups can then undergo alkylation in MeOH or byMel; to provide suksdorf in analogs according to formula (II) of thepresented invention.

Optically pure ester derivative compounds 8-11, 14-21, 33 and 34according to formula (I) can be obtained using an optically active acylchloride or acid a-hydride as presented in scheme 3. The products arediastereosomers, which can be separated with repeated chromatography.

Compounds, represented by formula (III), can be prepared from thefollowing commercially available starting materials 34 and 35, accordingto the procedures as for preparing compounds according to formula (I) aspresented herein.

The following starting materials are also prepared by the proceduredescribed in the literature (E. A. Clarke and M. F. Grundon, J. Chem.Soc., 1964,348), which can also be used to prepare compounds accordingto formula (III), according to known method steps.

Formula (IV)

A commercially available starting material 43 can be used to preparecompounds according to formula (IV), using known methods steps, e.g., aspresented herein.

Formula (V)

Starting materials for the compounds represented by formula (V) can beobtained by the reduction of the intermediate of (I), i.e., seselin (2),by reduction with diisobutylaminum hydride (DIBAL). The same procedureas for (I) will give the product 45 as shown by the formula (V), aspresented herein, or according to other known method steps.

Formula (VI)

A procedure for preparing seselin can be applied to phenols, such asresorcinol or orcinol, for the synthesis of the compounds as shown byformula (IV), according to known method steps.

Formula (VIII)

Procedures for synthesis of couromones [R. G. Cooker et al., Aus. J.Chem., 24, 1257 (1971); A. Ueno et al., Chem. Pharm. Bull., 26, 2407(1978)] can be applied for preparing the starting material for thecompounds represented by formula (VI), according to known method steps.

Formula (X)

The following commercially available starting material 49 can be usedfor the synthesis of (X) by the procedures as for (I), or according toknown method steps.

Formula (XII)

The following compounds 50 and 51 are commercially available as thestarting materials for the desired compounds (XII), according to knownmethod steps.

Formula (XIV)

Reduction of the following commercially available compound 52 will yieldthe starting compound for preparing compounds according to formula(XIV), as presented herein for (I) and/or according to known methodsteps.

Formula (XV)

The following compounds 53 and 54 are commercially available startingmaterials for preparing compounds according to formulae (XV), accordingto known method steps.

Formula (XVI)

The compounds represented by formula (XVI) can be prepared from thecommercially available 5,7-dihydroxycoumarin by the procedure as for(I), and/or according to known method steps.

Formula (XVII)

Reduction of the commercially available 7-nitro-3,4-benzocoumarin willyield an amine derivative, which can be further treated as for (T) togive a compound 55 according to formula (XVII), according to knownmethod steps.

Formula (XVIII)

Noracronvcine derivatives can be prepared according to the proceduredescribed in the literature (j. Ilubucek et al., Aust. J. Chem., 23,1881 (1970), which will be further treated by a similar procedure as for(I) giving compound according to formula (XVIII), according to knownmethod stews.

Formula (XIX)

The following compounds 57 and 58 can be used as commercially availablestating materials for preparing compounds according to formula (XIX),according to known method steps.

Formula (XX)

A commercially available substituted phenol, i.e., orcinol, olivetol,etc., can be used as a starting material for the compounds according toformula (XX), according to known method steps.

One particularly useful compound, identified here as XL-3-44 (compound3Ca), can be prepared as shown in Scheme 2A

(1) A mixture of 5 mmol of the 7-hydroxycoumarin derivative compound,1Ca and 1Cb, 12.5 mmol of potassium carbonate, 2.5 mmol potassiumiodide, and excess 2-methyl-2-chloro-3-butyne in 50 mL dimethylformamide (DMF) was stirred and heated at 60° C. for 2-3 days. Thepotassium carbonate was filtered out, and the reaction mixture wasconcentrated in vacuo. The residue was poured into ice water and leftovernight. The off- white solid product was collected by filtration. Theyield was 34-50%.

(2) The product of step (1) in N,N-diethylaniline was heated to boilingfor eight hours. After a general conventional work-up procedure, theyield of compound 2C was 60-75%.

(3) A mixture of 0.005 mmol of (DHQ)₂-PYR, 0.75 mmol K₃Fe(CN)₆, 0.75mmol K₂CO₃, 0.005 mmol of K₂OsO₂(OH)₄, 2.5 mL t-butyl alcohol/water, 1:1v/v, and 0.25 mmol compound 2C was stirred at 0° C. for 3-5 days. Then,NaS₂O₅, water and chloroform were added to the mixture, which wasstirred at room temperature for 0.5 hour. The organic phase wasseparated, and the water phase was extracted three times with CHCl₃. Theorganic phases were combined and the solvent was removed in vacuo.. Theresidue was the desired diol product.

(4) After the crude diol was dried, it was reacted directly with excess(−)-(S)-camphanoyl chloride in pyridine and methylene chloride at roomtemperature for 48 hours. After a general conventional work-upprocedure, the diester product, 3Ca, was obtained and was purified byTLC using hexane/ethyl acetate 3:1. The yield was 50S The structure of3Ca was determined by ¹H- NMR, MS, IR and elemental analyses. Theenantiomeric excess was determined by ¹H-NMR analysis of thebis(−)-camphanic esters.

Testing HIV activity in vitro

The following are examples of methods which can be used to screensuksdorfin analogs according to Formula G-1, G-2, and/or one or more of(I)-(XX), for determining at least one therapeutic utility and/ormechanism of action as an anti-viral compound, such as anti-HIVcompound; without undue experimentation, based on the teaching andguidance presented herein.

First various concentrations of suksdorf in analogs can be incubatedwith a chronically HIV-1 infected T cell line, e.g., ACH-2, and achronically HIV-1 infected monocytic cell line, e.g., U1. These celllines are useful in predicting if suksdorfin analogs of the presentinvention could induce virus expression in vivo when given to anindividual who is latently infected with HIV and not actively expressingvirus. In addition, when these two cell lines are incubated with thephorbol ester, PMA, HIV-1 expression is increased. Since suksdorfinanalogs of the present invention can inhibit virus replication during anacute HIV-1 infection of H₉ cells, it will be of interest to determineif it can also suppress HIV-1 expression from these two chronicallyinfected cell lines when they are stimulated with PMA.

Suksdorf in analogs of the present invention can be tested with othercell types (e.g., freshly isolated cells and/or cell lines) which areinfected with HIV. Freshly isolated monocyte/macrophages and peripheralblood mononuclear cells (PBMCs) can be infected with a monotropicisolate of HIV-1, Ba-L and/or a laboratory isolate (e.g., IIIB) ofHIV-1, respectively. In addition, virus suppression can be evaluatedwhen a suksdorf in analog is added to acutely HIV-1 (IIIB isolate)infected monocytic cell line, U937, and/or the HIV-2 (D194 isolate)infected T cell line, HUT-78. These studies will determine if thesuppressive effect of various suksdorfin analogs are specific to aparticular cell phenotype or a virus isolate.

Other studies can also be used to screen for the mechanism of action(MOA) of suksdorf in analogs according to at least one of formula (G-1),(G-2), and (I)-(XX), e.g., by:

(a) determining if the compound is capable of inactivating HIV-1 byculturing suksdorfin with HIV-1 for 1 hour before adding the virus to H₉cells;

(b) determining if the compounds' MOA is by competing with HIV for thesame receptor (CD4) on the cell surface. This can be tested by addingHIV-1, suksdorfin analogs and H₉ cells together and then monitoring theamount of virus produced in the presence and absence of suksdorfinanalogs;

(c) H₉ cells will also be pretreated with suksdorf in analogs todetermine if the effect of the drug is on the cells or on the virus.

(d) Molecular biology studies, wherein DNA and/or RNA levels can bemeasured in cells that had been treated with various concentrations ofsuksdorfin. This will be preferred where negative results are obtainedfrom one or more of methods (a)-(c). Both cellular and/or viralregulatory elements can be examined.

Suksdorfin analogs can also be tested in the presence of nucleosideanalogs (AZT, ddI, ddC) or other accepted anti-HIV agents, to determineif suksdorf in analogs are synergistic with any of these currentlylicensed anti-retroviral agents which can ultimately enhance theirindividual suppressive capability especially at lower concentrations.

A suksdorfin analog of the present invention can be used for treatmentof retroviral (e.g., HIV) infection either alone, or in combination withother modes of therapy known in the art. Such modes of therapy caninclude chemotherapy with drugs, such as, but not limited to, at leastone of AZT, ddC, ddA, ddT, ddI, or any other anti-retroviral antibodiesin combination with each other, or associated with a biologically basedtherapeutic, such as, for example, soluble CD4, antibodies to CD4, andconjugates of CD4 or anti-CD4, or as additionally presented herein.

Because suksdorfin analogs of the present invention are relatively lessor substantially non-toxic to normal cells, their utility is not limitedto the treatment of established retroviral infections. For example, asuksdorfin analog according to formulae (I) to (XX) can be used in thetreatment of blood products, such as those maintained in blood banks.The nation's blood supply is currently tested for antibodies to HIV.However, the test is still imperfect and samples which yield negativetests can still contain HIV virus. Treating blood and blood productswith the proteins and derivatives of the present invention can add anextra margin of safety, to kill any retrovirus that can have goneundetected.

Pharmaceutical Compositions

Pharmaceutical compositions of the present invention can comprise atleast one suksdorfin analog according to at least one of formulae (I),(II), (G-1), (G-2), and (III)-(XX). Pharmaceutical compositionsaccording to the present invention can also further comprise otheranti-viral agents, such as, but not limited to, AZT, ddI,2′-β-fluoro-ddI, ddA, ddG, ddC, 2′-β-fluoro-ddC , d4T, AzddU,phosphonylmethoxyethyl-adenine, or soluble CD4, or immunomodulators,e.g., as presented below. For a review of therapeutic agents in HIVinfection, see, e.g., Mitsuya, H. et al., FASEB J. 5:2369-2381 (1991),which reference is hereby incorporated by reference.

Additional suitable antiviral agents for optimal use with a coumarincompound of the present invention can include, but are not limited to,AL-721 (lipid mixture) manufactured by Ethigen Corporation and MatrixResearch Laboratories; Amphotericin B methyl ester; Ampligen (mismatchedRNA) developed by DuPont/HEM Research; anti-AIDS antibody (NisshonFood); AS-101 (heavy metal based immunostimulant); AZT (azidothymidinelRetrovir/Zidovudine) manufactured by Burroughs Wellcome; Betaseron(β-interferon) manufactured by Triton Biosciences (Shell Oil); butylatedhydroxytoluene; Carrosyn (polymannoacetate) Castanospermine; Contracan(stearic acid derivative); Creme Pharmatex (contains benzalkoniumchloride) manufactured by Pharmelac; CS-87 (5-unsubstituted derivativeof Zidovudine); Cytovene (ganciclovir) manufactured by SyntexCorporation; DDC (dideoxycytidine) manufactured by Hoffann-La Roche andother nucleoside analogues; dextran sulphate; D-penicillamine(3-mercapto-D-valine) manufactured by Carter-Wallis and DegussaPharmaceutical; Foscarnet (trisodium phosphonoformate) manufactured byAstra AB; fusidic acid manufactured by Leo Lovens; glycyrrhizin (aconstituent of liquorice root): HPA-23(ammonium-21-tungsto-9-antimonate) manufactured by Rhone-Poulenc Sante;human immunevirus antiviral developed by Porton Products International;Ornidyl (eflbrnithine) manufactured by Merrell-Dow; Nonoxinol;pentamidine isethionate (PENTAM-300) manufactured by Lypho Med; PeptideT (octapeptide sequence) manufactured by Peninsula Laboratories;Phenytoin (Warner-Lambert); Ribavirin; Rifabutin (ansamycin)manufactured by Adria Laboratories; rsT4 (recombinant soluble T4)manufactured by Biogen, Genentech and Smith Kline & French; Trimetrexatemanufactured by Warner-Lambert Company; SK-818 (germanium-derivedantiviral) manufactured by Sanwa Kagaku; suramin and analogues thereofmanufactured by Miles Pharmaceuticals; UA001 manufactured by Ueno FineChemicals Industry; Wellferon (α-interferon) manufactured by BurroughsWellcome; Zovirex (acyclovir, AZT) manufactured by Burroughs Wellcome.

Pharmaceutical compositions of the present invention can also furthercomprise immunomodulators. Suitable immunomodulators for optional usewith a coumarin compound of the present invention in accordance with theinvention can include, but are not limited to: ABPP (Bropirimine):Ampligen (mismatched RNA) (DuPont/HEM Research); anti-human interferon-αantibody (Advance Biotherapy and Concepts); anti-AIDS antibody (NisshonFood): AS-101 (heavy metal based immunostimulant), ascorbic acid andderivatives thereof; interferon-β; Carrosyn (polymannoacetate); Ciamexon(Boehringer-Mannheim); Cyclosporin; Cimetidine; CL-246,738 (AmericanCyanamid); colony stimulating factors, including GM-CSF (Sandoz;Genetics Institute; dinitrochlorobenzene; interferon-α;interferon-gamma; glucan; hyperimmune gamma-globulin (BAYER); IMREG-1(leucocyte dialyzate) and IMREG-2 (IMREG Corp.); immuthiol (sodiumdiethylthiocarbarmate) (Institut Merieux); interleukin-1 orinterleukin-2 (Cetus Corporation; Hoffman-La Roche; Immunex);isoprinosine (inosine pranobex); Krestin (Sankyo); LC-9018 (Yakult);lentinan (Ajinomoto/Yamanouchi); LF-1695 (Fournier);methionine-enkephalin (TNI Pharmaceuticals; Sigma Chemicals); MinophagenC; muramyl tripeptide, MTP-PE (Ciba-Geigy); naltrexone (“Trexano”(DuPont); Neutropin; RNA immunomodulator (Nippon Shingaku); shosaikotoand ginseng; thymic humoral factor; TP-5 (Thymopentin) (OrthoPharmaceuticals; Thymosin fraction 5 and Thymosin 1; Thymostimulin; TNF(tumor necrosis factor) manufactured by Genentech; and vitamin Bpreparations.

The preferred animal subject of the present invention is a mammal. Bythe term “mammal” is meant an individual belonging to the classMammalia. The invention is particularly useful in the treatment of humansubjects.

By the term “treating” is intended the administering to subjects of asuksdorfin analog or derivative for purposes which can includeprevention, amelioration, or cure of a retroviral-related pathology.

Medicaments are considered to be provided “in combination” with oneanother if they are provided to the patient concurrently or if the timebetween the administration of each medicament is such as to permit anoverlap of biological activity.

In one preferred embodiment, at least one suksdorfin analog comprises asingle pharmaceutical composition.

Pharmaceutical compositions for administration or diagnosis of thepresent invention can comprise at least one suksdorf in analog accordingto at least one of Formulae (G-1), (I) and/or (II) in pharmaceuticallyacceptable form optionally combined with a pharmaceutically acceptablecarrier. Such compositions can be administered by any means that achievetheir intended purpose. Amounts and regimens for the administration of asuksdorf in analog of the present invention can be determined readily bythose with ordinary skill in the clinical art of treating a retroviralrelated pathology.

For example, administration can be by parenteral, such as subcutaneous,intravenous, intramuscular, intraperitoneal, transdermal, or buccalroutes. Alternatively, or concurrently, administration can be by theoral route. The dosage administered will be dependent upon the age,health, and weight of the recipient, kind of concurrent treatment, ifany, frequency of treatment, and the nature of the effect desired.

Compositions within the scope of this invention include all compositionswherein at least one suksdorfin analog according to formula (I), (II) or(G-1) is comprised in an amount effective to achieve its intendedpurpose. While individual needs vary, determination of optimal ranges ofeffective amounts of each component is within the skill of the art.Typical dosages comprise 0.1 to 100 mg/kg/body weight. The preferreddosages comprise 1 to 100 mg/kg/body weight. The most preferred dosagescomprise 10 to 100 mg/kg/body weight.

Therapeutic administration can also include prior, concurrent,subsequent or adjunctive administration of at least one additionalsukdorf in or other therapeutic agent, as an anti-viral or immunestimulating agent. In such an approach, the dosage of the second drugcan preferably be the same or different that as the dosage of the firsttherapeutic agent. Preferably, the drugs are administered on alternatedays in the recommended amounts of each drug.

Administration of a compound of the present invention can alsooptionally include previous, concurrent, subsequent or l adjunctivetherapy using immune system boosters or immunomodulators. In addition tothe pharmacologically active compounds, a pharmaceutical composition ofthe present invention can also contain suitable pharmaceuticallyacceptable carriers comprising excipients and auxiliaries whichfacilitate processing of the active compounds into preparations whichcan be used pharmaceutically. Preferably, the preparations, particularlythose preparations which can be administered orally and which can beused for the preferred type of administration, such as tablets, dragees,and capsules, and also preparations which can be administered rectally,such as suppositories, as well as suitable solutions for administrationby injection or orally, contain from about 0.01 to 99 percent,preferably from about 20 to 75 percent of active compound(s), togetherwith the excipient.

Pharmaceutical preparations of the present invention are manufactured ina manner which is itself known, for example, by means of conventionalmixing, granulating, dragee-making, dissolving, or lyophilizingprocesses. Thus, pharmaceutical preparations for oral use can beobtained by combining the active compounds with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Suitable excipients are, e.g., fillers such as saccharide, for example,lactose or sucrose, mannitol or sorbitol, cellulose preparations and/orcalcium phosphates, for example, tricalcium phosphate or calciumhydrogen phosphate, as well as binders such as starch paste, using, forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose,sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,disintegrating agents can be added such as the above-mentioned starchesand also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar,or alginic acid or a salt thereof, such as sodium alginate. Auxiliariesare, above all, flow-regulating agents and lubricants, for example,silica, talc, stearic acid or salts thereof, such as magnesium stearateor calcium stearate, and/or polyethylene glycol. Dragee cores areprovided with suitable coatings which, if desired, are resistant togastric juices. For this purpose, concentrated saccharide solutions canbe used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquersolutions and suitable organic solvents or solvent mixtures. In order toproduce coatings resistant to gastric juices, solutions of suitablecellulose preparations such as acetylcellulose phthalate orhydroxypropymethyl-cellulose phthalate are used. Dye stuffs or pigmentscan be added to the tablets or dragee coatings, for example, foridentification or in order to characterize combinations of activecompound doses.

Other pharmaceutical preparations which can be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain the active compounds in the form of granules whichcan be mixed with fillers such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds are preferablydissolved or suspended in suitable liquids, such as fatty oils or liquidparaffin. In addition, stabilizers can be added.

Possible pharmaceutical preparations which can be used rectally include,for example, suppositories which consist of a combination of the activecompounds with a suppository base. Suitable suppository bases are, forexample, natural or synthetic triglycerides, or paraffin hydrocarbons.In addition, it is also possible to use gelatin rectal capsules whichconsist of a combination of the active compounds with a base. Possiblebase materials include, for example, liquid triglycerides, polyethyleneglycols, or paraffin hydrocarbons.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for example,water-soluble salts. In addition, suspensions of the active compounds asappropriate oily injection suspensions can be administered. Suitablelipophilic solvents or vehicles include fatty oils, for example, sesameoil, or synthetic fatty acid esters, for example, ethyl oleate ortriglycerides. Aqueous injection suspensions that can contain substanceswhich increase the viscosity of the suspension include, for example,sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally,the suspension can also contain stabilizers.

A pharmaceutical formulation for systemic administration according tothe invention can be formulated for enteral, parenteral or topicaladministration. Indeed, all three types of formulation can be usedsimultaneously to achieve systemic administration of the activeingredient.

Suitable formulations for oral administration include hard or softgelatin capsules, dragees, pills tablets, including coated tablets,elixirs, suspensions, syrups or inhalations and controlled release formsthereof.

Solid dosage forms in addition to those formulated for oraladministration include rectal suppositories

At least one suksdorfin analog can also be administered in the form ofan implant.

Suitable formulations for topical administration include creams, gels,jellies, mucilages, pastes and ointments. The compounds can also beformulated for transdermal administration, for example, in the form oftransdermal patches so as to achieve systemic administration.

Suitable injectable solutions include intravenous subcutaneous andintramuscular injectable solutions. At least one suksdorfin analog canalso be administered in the form of an infusion solution or as a nasalinhalation or spray.

Having now generally described the invention, the same will be morereadily understood through reference to the following examples which areprovided by way of illustration, and are not intended to be limiting ofthe present invention, unless specified.

EXAMPLE I Isolation and Purification of Suksdorf in Analog of thePresent Invention

Suksdorfin was obtained as colorless needles (m.p. 140-141° C.) bysilica gel chromatography of the active hexane fractions. Its molecularformula was determined to be C₂₁H₂₄O₇ by high resolution massspectroscopy, and a comparison of the UII, IR, and ¹H-NMR spectral datawith those described in the literature identified 1 as suksdorfin, whichhad been previously isolated from this same plant by Willette and Soine(Willette, R. E.; Soine, T. O. J. Pharm. Sci., 1962, 51, 149).

Suksdorf in demonstrated potent inhibitory activity against HIV-1replication in acutely infected H₉ cells with an EC₅₀ of 1.3 μM asdetermined by a p24 antigen ELISA assay and it inhibited uninfected H₉cell growth with an IC₅₀ of >52μM (Table 1). The therapeutic index (IC₅₀for cell growth inhibition divided by EC₅₀ for HIV inhibition) forsuksdorfin compound 1 was >40. In comparison, the therapeutic index ofdideoxyinasins (ddI), a dideoxynucleaside which inhibits reversetranscriptase, when tested in our assay system was only 10-fold greater(>400) than that observed with suksdorfin.

In order to elucidate structure-activity relationships, theHIV-replication inhibitory effects of ten coumarins, which are isolatedfrom various plant sources (Soine, T.; O. J. Pharm. Sci., 1964, 53,231), was determined and compared with that of 1. The compounds includean additional dihydroseselin type angular pyranocoumarin, 2 (pteryxin),a dihydro-angelicin type angular coumarin, 3 (columbianadin), threedihydroangelicin linear furanocourins, 4 (nodakenetin), 5 (nodakenin),and 6 (acetylnodakenin), four psoralen type linear furanocoumarins, 7(imperatorin), 8 (bergapten), 9 (isoimperatorin), and 10(oxypeucedanin), and a dicoumaryl ether, 11 (daphnoretin).

As shown in Table 1, only 1 showed potent anti-HIV-1 activity atnontoxic concentrations. All other compounds (2-11) were either inactiveor were less active and more toxic. The 4′-isovaleryl group of 1 wasimportant for selective HIV-1 inhibition. Replacement of this group withan angeloyl moiety as in pteryxin (2) in-creased the toxicity by 5-foldand slightly reduced anti-HIV-l activity. The furanocoumarins (3-10)were inactive or active only at toxic concentrations, (e.g., thetherapeutic index of 3 was >1.3). The dicoumaryl ether (11) showed noactivity.

TABLE 1 HIV Inhibition⁵ by Suksdorfin (1) and Related Compounds (2-11).Therapeutic Compound IC₅₀ (μM)^(a) EC₅₀ (μM)^(b) Index 1 Suksdorfin >521.3 >40 2 Ptyeryxin >10.4 4.6 >3.7 3 Columbianadin >6.1 4.6 >1.3 4Nodakenetin ND^(c) Inactive^(d) ND 5 Nodakenin ND Inactive ND 6Acetylnoda- ND Inactive ND kenin 7 Imperatorin >74.1 11.1 >6.7 8Bergapten >92.6 30.1 >3.1 9 Isoimperatorin >185.2 40.7 >4.6 10Oxypeucedanin >69.9 31.5 >2.2 11 Daphnoretin ND Inactive ND Whencompound XL-3-44 was tested for HIV inhibition in the manner describedabove, the IC₅₀ (μg/ml) was >100, and further delutions must be made toobtain EC₅₀ (μg/ml) and Therapeutic Index Values. ^(a)Concentrationwhich inhibits uninfected cell growth by 50% ^(b)Concentration whichinhibits viral replication by 50% ^(c)ND - not determined ^(d)Nosuppression of HIV-1 replication in H9 cells

EXAMPLE II In vitro HIV Inhibition Activity Assays

HIV inhibition assay. The HIV inhibition was measured as describedherein. Briefly, H₉ cells, a T cell line, (3.5×10⁶ cells/ml) wereincubated in the presence or absence of HIV-1 (IIIB strain, 0.01-0.1TCID₅₀/cell) for 1 hour at 37° C. Cells were washed thoroughly andresuspended at a final concentration of 2×10⁵ cells/ml in the presenceor absence of compound. After incubation for 3-4 days at 37° C., thecell density of uninfected cultures was determined by cell count toassess toxicity of the drug. An aliquot of each cell-free supernatantwas assayed by p24 antigen ELISA to quantitate the amount of HIV-1present in the infected cultures. Test compounds were considered to beactive at a particular concentration if p24 antigen levels were lessthan 70% of infected, untreated controls and were nontoxic to uninfectedH₉ cells.

EXAMPLE III Synthesis of Suksdorfin Analogs

Synthesis of Seselin (2) (Scheme 1)

The construction of the pyran ring from commercially available7-hydroxycoumarin (1) involved two steps, which have been described byHlubucek, et al. Aust. J. Chem. 24:2347 (1971). The crude product of thefirst step was used directly in the next rearrangement reaction, whichproduced seselin (2) in good yield. Seselin was then used as thestarting material for the synthesis of other pyranocoumarin derivativesas described below.

(±)-3′,4′-Di-O-acyl- cis-khellactone derivatives (Scheme 1). The3′,4′-di-O-acyl- cis-khellactone derivative compounds 12-21 can beprepared by two routes. In the first, seselin (compound 2) wasfunctionalized at the 3′,4′ positions by oxidation withm-chloroperoxybenzoic acid to give the (±)-3′-hydroxy-4′-O-acylderivative compound 3 (Schroeder et al, Chem. Ber. 92, 2388, (1959)).Tosic acid catalyzed dehydration transformed compound 3 to an opticallyinactive 3-keto derivative compound 4 (Willette et al J. Pharm. Sci. 51,149 (1962)). According to a literature method (S. N. Shanbhag et alTetrahedron, 21:3591 (1965)), treatment of compound 4 with leadtetraacetate in acetic acid should yield the racemic compound 5, despitethe low yield reported in this transformation. After saponification andreesterification at C-4′ to give a 3′-keto-4′-O-acyl intermediatecompound 6, the ketone can be reduced to a hydroxyl group with NaBH₄(Shanbhag, supra). Further esterification of this (±)-mono esterkhellactone with RCOCl or (RCO) 20 could furnish the desired(±)-di-O-acyl-khellactone derivatives, followed by carefulchromatographic separation of their cis racemic mixture.

In the second route, seselin compound 2 was oxidized with OsO₄ to givethe cis-khellactone intermediate compound 7 in good yield (Schroeder etal, supra). The 3′,4′-di-O-ester-cis-khellactone derivative compounds12-17, in which the two ester groups at 3′ and 4′ are identical, wereproduced using standard esterification conditions. However, by usingequal molar reagents and mild reaction conditions, selectiveesterification could be achieved giving the 3′-mono compounds 8,9* and4′-mono ester khellactone compounds 10,11* in a mixture with thediesters. Separation and further esterification of these mono estercompounds 8-11* using acetic anhydride yielded the desired(±)-3′,4′-di-O-acyl-cis-khellactone derivative compounds 18-21*, whichhave different ester moieties at the 3′ and 4′ positions. This methodhas fewer steps and gives better yields than the previous route throughcompound 4. However, OsO₄ is very toxic and expensive, which limits itsextensive use.

(±)-3′-O-acyl-jatamansinol derivatives (Scheme 2)

Jatamansinol derivatives were synthesized using a literature method(Murry et al Tetrahedron letters 27:4901 (1971)). A phenyl group wasintroduced at C-8 of 7-hydroxycoumarin (1) in a three-step sequence,which involved a Claisen rearrangement. Under slightly acidicconditions, cyclization of intermediate compound 23 furnishedjatamansinol compound 24. Using standard esterification conditions,(±)-3′-O-acyl-jatamansinol derivatives (compounds 25, 26) weresynthesized, as shown in Scheme 3.

(±) 3′,4′-Di-O-acyl-trans-khellactone derivatives and3′-O-alkyl-4′-O-acyl-trans-khellactone derivatives (Scheme 4)

Preparation of the 3′,4′-trans derivatives proceeds from intermediatecompound 3. Compound 3 was esterified by treatment with the appropriateacyl chloride or acid anhydride to produce the3′,4′-di-O-acyl-trans-khellactones (compounds 27,28,33,34). Reaction ofcompound 3 with various alkylating reagents (MeI, benzyl bromide,dihydropyran) gave the 3′-alkyl intermediate compounds 29-32.Saponification of these compounds gave the 3′-alkyl-4′-hydroxyderivative compounds 35-38. After esterification with an acyl chlorideor acid anhydride, the (±)-3′-O-alkyl-4′-O-acyl-trans-khellactonederivative compounds 39-42 were synthesized.

(±)-Benzodihydropyran derivatives (Scheme 4)

The lactone ring in compound 3 or in the 3′,4′-diacyl-trans derivativeswas abolished using a basic hydrolysis procedure to give new (±)-benzodihydropyran compound 43. The base (KOH, Ag₂O, or NaH) cleaves thelactone ring and the ester groups. The free acid or the hydroxyl groupscan then undergo alkylation by MeI.

Optically pure ester derivatives (compounds 8-11*, 14-21*, 33, 34*) wereobtained using an optically active acyl chloride or acid anhydride. Theproducts are diastereoisomers, which can be separated with repeatedchromatography.

EXAMPLE II Anti-HIV Activity of Suksdorfin Analogs Against HIV-infectedH₉ Lymphocytes

The inhibitory activities of the synthesized suksdorfin analogs againstHIV-replication in H₉ lymphocytes were examined. The compounds includecis- (compounds 8-15) and trans- (compounds 27-32) khellactonederivatives, jatamansinol derivatives (compounds 25-26), and opticallypure cis- (compounds 16-17) and trans- (compounds 44-45) khellactonederivatives.

As shown in Table 3, compound 16 exhibited potent anti-HIV activity. TheED⁵⁰ value of compound 16 is at least 0.00041 AM and its therapeuticindex is over 78,125 but less than 390,625. This activity is much betterthan that of suksdorfin. Since the ED₅₀ value and therapeutic index ofAZT in this assay system are 0.04 μM and 50,000, respectively, theanti-HIV activity of compound 16 is more potent than that of AZT.

The diastereomer of compounds 16 (17), as well as compounds 44 and 45,which are trans-khellactone derivatives with same acyl groups, showedmuch less activity than that of compound 16.

TABLE 3 HIV Inhibition by Synthesized Suksdorfin Derivatives TherapeuticCompound IC₅₀ (μM) EC₅₀ (μM) Index 8 and 9 ND >57.8 ND 10 and 11ND >57.8 ND 12 ND >289 ND 13 ND >232 ND 14 and 15 >47 but <233 7.0 >6.7but <33.3 25 ND >69 ND 26 ND >12 ND 27 ND >45 ND 28 10 8.3 1.2 29 >48241 >0.2 30 >8 but <41 6.1 >1.3 but 6.7 31 ND >41 ND 32 >40 but <2008.3 >5 but <25 16 >32 but <160 0.00041 >78,125 but <390,625 17 1,70051 >33.3 44 >6.4 but <32 >6.4 but <32 >1 45 <32 32 >1 AZT 2000 0.0450,000

EXAMPLE II Activity of Suksdorpin Against HIV-Infected ACH-2 And U1Cells

Effects of suksdorfin analogs on Chronically HIV-1 infected cells. Theexperimental design is as follows: The phorbol ester, PMA (10⁻⁸M) andvarious concentrations of suksdorfin were either added or not added toboth the chronically HIV-1 infected T cell line (ACH-2) and to thechronically HIV-1 infected monocytic cell line (U1). Cell-freesupernatant was collected 72 hours post culture for p24 antigen ELISA.

The chronically HIV-1 infected cell lines, ACH-2 and U1 have been usedextensively in the literature. When either cell line is cultured withPMA or various cytokines the level of HIV-1 expression as determined byp24 antigen ELISA is increased. Since suksdorfin suppressed virusreplication in acutely HIV-1 infected H₉ cells, it was important todetermine if it would have an effect on chronically HIV-1 infectedcells. In addition, these two cell lines are helpful in predictingwhether a drug might increase the in vivo replication of HIV in anindividual who is latently virally-infected.

Therefore, the questions which this experiment addressed were thefollowing:

1. Does suksdorf in cause an increase in the amount of virus replicationfrom either chronically T or monocyte/macrophage infected cell line. Theanswer is no. This information is important to the FDA, since they willnot permit administering an agent in vivo to an individual that mightcause an increase in virus replication.

2. Does suksdorfin alter the amount of virus replication fromPMA-stimulated chronically HIV-1 infected cells? The answer is no. Therewas no significant alteration in the level of virus expression asmeasured by p24 antigen ELISA when PMA was added to cells which werealso cultured in the presence of suksdorfin. Suksdorfin did not increasethe amount of virus produced by PMA alone. The above determinations werebased in part on the data presented in Table 4.

TABLE 4 Suksdorfin ACH-2 Cells U1 Cells Concentration −PMA +PMA −PMA+PMA 0 μg/ml 3,676 pg/ml 52,122 pg/ml 0 pg/ml 6,963 pg/ml 20 μg/ml 4,541pg/ml 49,914 pg/ml 0 pg/ml 5,096 pg/ml 4 μg/ml 4,723 pg/ml 61,235 pg/ml0 pg/ml 9,728 pg/ml 0.8 μg/ml 3,821 pg/ml 55,910 pg/ml 0 pg/ml 7,360pg/ml 0.16 μg/ml 3,688 pg/ml 50,775 pg/ml 0 pg/ml 6,611 pg/ml

There was a higher background in the ACH-2 cells (3,676 pg/ml) thancompared to the Ul cells (0 pg/ml). A known viral inducer, when added toeach cell line, caused a significant increase in the amount of p24antigen in those cultures.

EXAMPLE III Combination Study of Suksdorfin with AZT, ddI and ddC.

The data presented in Table 5 show toxicity data on a suksdorfin. TheIC₅₀ value has decreased from >20 but <100 to >4 but <20 and the EC₅₀value has increased from 0.5-0.8 to 1.5-2.8 μg/mi.

Suksdorfin is found to act synergistically with AZT, ddI and ddC. The 20μg/ml concentration of suksdorfin was toxic to H₉ cells. The 4 μg/mlconcentration of suksdorf in inhibited HIV-1 replication by 649 but whenit was added to HIV-1 infected cultures containing AZT (0.0001 μg/ml)the EC₅₀ concentration decreased by 400-fold and the TI value increasedby 400-fold. Likewise, 4000-fold less ddI was needed when 4 μg/ml ofsuksdorfin was present in the cultures as when ddI was used alone.Forty-fold less ddC was needed when it was added to cultures containing4 μg/ml of suksdorfin. This is significant data demonstrating thatsuksdorfin is expected to be useful in increasing the anti-HIV activityand/or decreasing the toxicity of these other FDA-approved drugs.

TABLE 5 Therapeutic Compound Purity IC₅₀ (μg/ml) EC₅₀ (μg/ml) IndexSuksdorfin pure >4 but <20 2.8 >1.4 but <7.1 AZT pure >1 0.04 >25 ddIpure >1 0.4 >2.5 ddC pure >1 0.004 >250 4 μg/ml pure >1 <0.0001 >10,000Suksdorfin + AZT μg/ml pure >1 <0.0001 >10,000 Suksdorfin + ddI μg/mlpure >1 <0.0001 >10,000 Suksdorfin + ddC

EXAMPLE IV Anti-HIV Activity of Suksdorfin

Suksdorf in was tested on peripheral blood mononuclear cells (PBMCS)which were stimulated for 3 days with PHA (1 ∥g/ml). The cells werecollected and then infected with the 20X stock HIV-1 (IIIB). This is thesame virus that is used in the drug screening assay. PBMCs were used forthe following reasons: (1) It is another type of T cell infection. (2)PMBCs are freshly isolated cells not a cell line as are H₉ cells. (3) Weneed to know if the effects of suksdorfin were limited to only an acuteHIV-1 infection of a T cell line such as H₉ cells. After the cells wereinfected with HIV-1, the cells were washed and then placed in mediumwith the cytokine, interleukin 2 (IL-2). IL-2 is needed to keep thecells activated which is necessary also for virus replication.

Suksdorfin was also tested on an acute HIV-1 infection of thepromonocytic cell line, U937. This was done again to determine drugspecificity but this time on a monocytic cell line.

As the data indicates, suksdorfin can suppress an acute HIV-1replication in fresh PBMCs (a T cell infection) and in U937 cells (amonocytic cell line). The data from the PBMC infection correlates withother data in which H₉ cells (a T cell line) were infected with HIV-1and then suksdorf in was added. The EC₅₀ was 1.5, as presented in Table6. The EC50 value determined from the U937 cells was approximately onethird of that for the PBMCs.

TABLE 6 IC₅₀ EC₅₀ Therapeutic Compound Purity (μg/ml) (μg/ml) IndexSuksdorfin + pure PBMCs >4 but <20 1.5 >2.7 but <13.3 U937 >200.58 >34.5 cell line

EXAMPLE V Anti-HIV Activity Results for Suksdorfin Analog Compounds

Table 7 shows results from 4 separate assays as presented in the aboveexamples on compound 16 when tested alone and data from 1 experimentwhen tested in combination with either AZT, ddI, or ddC.

Compound 16 was tested for its ability to inhibit HIV-1 replication inH₉ cells. An activity was found of 256 pg/ml (0.0041 μM). The IC₅₀ range(>32 but <160) was consistent and showed low toxicity. EC₅₀ results: 3assays demonstrated significant suppression. During the assays the agentmediated 44% and 35% suppression at 0.000256 μg/ml, respectively. TheEC₅₀ value was at least about 0.000256 μg/ml (256 pg/ml [0.00041 μM).Based on an EC₅₀ value of 256 pg/ml, the TI was >78,125 but <390,625 for16 (LH₇₀CI-4L).

TABLE 7 16 IC₅₀ (μg/ml) EC₅ (μg/ml) Therapeu- (LH70C1-4L) Purity [μM][μM] tic Index pure >20 but <100 0.000256 >78,125 (>32 but (0.00041) but<160) >390,625

Results from chronic U1 experiment with 16

Compound 16 was also assayed on ACH-2 (chronically HIV-1 infected T cellline). U1 cells are also chronically HIV-1 infected cells but they arefrom the monocytic cell line, U937. The data presented in Table 8indicates the following points:

Compound 16 (without PMA) did not induce the U1 cells to make virus.This was also the same for AZT. The amount of HIV-1 present in thesesupernatants is very low and not significantly above assay background.The fact that the drμg did not induce virus replication is importantsince individuals tend to be latently infected with HIV; therefore, itis important that a drug not increase in vivo viral burden duringtherapy, as shown by this data.

Compound 16 (with PMA) did not suppress virus replication. The resultswere identical to AZT. This is not surprising since AZT does not have aneffect on chronically HIV infected cells (in the literature) sincereverse transcription has already occurred.

There was good virus expression in the control U1 sample as compared tobackground. The various drag-treated samples were not significantlydifferent than control. For there to be a significant increase, theamount of p24 antigen in the supernatant needs to increase at least 4-5fold. This was not the case.

Results of testing the ability of compound 16 to suppress virusreplication during an HIV-2 infection of HUT-78 cells.

During this experiment, HIV-2 was used. The basic assay system isidentical to that used for HIV-1 except that a different virus stock wasused and rather than a p24 antigen ELISA determination a reversetranscriptase assay was used to detect the presence of the virus.

As the data indicates in Table 9, compound 16 had no effect on the virusreplication of HIV-2. This data will help in designing futureexperiments especially as they relate to animal model system for testingthe in vivo activity of compound 16. Compound 16 will also be tested insimian immunodeficiency virus (SII)-infected cells since SII and HIV aresimilar.

AZT was used as a positive drug control and it inhibited HIV-2replication.

TABLE 8 Sample P24 pg/ml Identification −PMA +PMA U1 control 0 5660 U1 +LHJ70C1-4L 16 [μM] (20 μg/ml) [32] 95 9530 (4 μg/ml) [6.4] 41 8742 (0.8μg/ml) [1.3] 88 8390 (0.16 μg/ml) [0.26] 76 7162 (0.032 μg/ml) [0.051]101 8090 (0.0064 μg/ml) [0.010] 90 6419 (0.00128 μg/ml) [0.0021] 99 6335(0.00025 μg/ml) [0.00040] 78 7757 (0.0000512 μg/ml) [0.000084] 56 8710(0.0000102 μg/ml) [0.000016] 52 7328 U1 + AZT (10 μg/ml) [37] 97 8653 (1μg/ml) [3.7] 72 7898 (0.1 μg/ml) [0.37] 53 4363 (0.01 μg/ml) [0.037] 509626

TABLE 9 Sample RT Activity Identification (CPM) LH70C1-4L at: [μM] 4μg/ml [6.4] 13,664 0.8 μg/ml [1.3] 14,871 0.16 μg/ml [0.26] 11,535 0.032μg/ml [0.051] 16,463 0.0064 μg/ml [0.010] 18,403 0.00128 μg/ml [0.0021]9,568 0.000256 μg/ml [0.00040] 15,625 0.0000512 μg/ml [0.000084] 16,9370.0000102 μg/ml [0.000016] 13,992 AZT at: [μM] 10 μg/ml [37] 1,990 1μg/ml [3.7] 1,826 0.1 μg/ml [0.37] 2,662 0.01 μg/ml [0.037] 1,919Infected Control (no drμg) 17,264 Uninfected Control 719

Results of testing the ability of compound 16 to suppress virusreplication during an HIV-1 infection of primary monocytes.

In order to determine if compound 16 suppressive activity was limited toonly fresh T cells infected with HIV-1, elutriated monocytes wereinfected with HIV-1 and then cultured with various concentrations ofcompound 16 or AZT. As the data indicates in Table 10, 16 is also ableto suppress HIV-1 replication in fresh elutriated monocytes. Thisillustrates that the effect of the drμg is not only limited to T cellsbut also can effect virally infected monocytes.

AZT was used as a positive drμg control and it inhibited HIV-1replication in the human monocytes.

TABLE 10 p24 antigen p24 antigen Sample (pg/ml) (pg/ml) IdentificationDay 17 Day 28 16 at: [μM] 20 μg/ml [32] 5 0 4 μg/ml [6.4] 6 0 0.8 μg/ml[1.3] 6 0 0.16 μg/ml [0.26] 7 0 0.032 μg/ml [0.051] 94 0 0.0064 μg/ml[0.010] 66 584 0.00128 μg/ml [0.0021] 306 208 0.000256 μg/ml [0.00040]70 760 0.0000512 μg/ml [0.000084] 52 824 0.0000102 μg/ml [0.000016] 491536 AZT at: [μM] 10 μg/ml [37] 0.1 0 1 μg/ml [3.7] 2 0 0.1 μg/ml [0.37]5 0 0.01 μg/ml [0.037] 7 0 0.001 μg/ml [0.0037] 100 0 0.0001 μg/ml[0.00037] 83 0 Infected Control (no drμg) 205 2944 Uninfected Control 714

TABLE 11 Sample P24 pg/ml Identification −PMA +PMA ACH-2 control 92825,572 ACH-2 + 16 at: [μM] (20 μg/ml) [3.2] 1509 24,858 (4 μg/ml) [6.4]1194 23,547 (0.8 μg/ml) [1.3] 976 20,183 (0.16 μg/ml) [0.26] 1174 21,865(0.032 μg/ml) [0.051] 1319 24,650 (0.064 μg/ml) [0.010] 955 24,364(0.00128 μg/ml) [0.0021] 811 22,344 (0.00025 μg/ml) [0.00040] 777 22,756(0.0000512 μg/ml) [0.000084] 659 16,079 (0.0000102 μg/ml) [0.000016] 66617,938 U1 + AZT (10 μg/ml) [37] 939 16,584 (1 μg/ml) [3.7] 904 17,088(0.1 μg/ml) [0.37] 942 10,621 (0.01 μg/ml) [0.037] 796 21,373

Results (Table 11) from adding compound 16 to the chronicallyHIV-infected T cell line, ACH-2, according to methods in above examples.ACH-2 are a chronically HIV-1 infected T cell line. It was derived fromA3.01 cells which is a subclone of the CEM cell line. The data belowindicates the following points:

There was a 27-fold induction of virus replication when PMA was added toACH-2 cells as compared to medium alone. This result indicatessuitability for in vivo treatment of HIV infection.

Compound 16 (without PMA) did not induce the ACH-2 cells to make virus.This was also the same for AZT. These cells make a greater quantity ofHIV-1 constitutively than do the Ul cells. However, there was nosignificant increase in the level of virus expression in the presence ofeither compound 16 or AZT as compared to medium alone. These are goodresults indicating suitability for in vivo treatment of HIV infection.

Compound 16 (with PMA) did not suppress virus replication. The resultswere identical to AZT. This is not surprising since AZT does not have aneffect on chronically HIV infected cells (in the literature) sincereverse transcription has already occurred. This data agrees with the U1results sent earlier this week.

The various drug-treated samples were not significantly different thanPMA-induced control. For there to be a significant increase, the amountof p24 antigen in the supernatant needs to increase or decrease at least4-5 fold.

Results (Table 12) from adding Suksdorfin to fresh monocytes infectedwith HIV-1.

The monocytes which were used for this experiment were obtained byadherence and not by elutriation; therefore, this cell population is notas pure as what was used for the 16 monocyte data above.

Suksdorfin at 20 and 4 μg/ml did suppress HIV-1 replication in freshmonocytes. This was more pronounced at day 12, which was approximatelythe peak of virus replication. AZT was used as the positive drug controland it was suppressive.

TABLE 12 Sample p24 pg/ml (% suppression) Identification Day 6 Day 12Day 18 Infected Control 59,648 270,541 105,882 Infected + Suksdorfin at:(20 μg/ml) 16,712 (72) 25,567 (91)  23,506 (78) (4 μg/ml) 48,748 (18)89,467 (67) 103,834 (0) (0.8 μg/ml) 53,043 (0) 163,656 (40) 130,970 (0)(0.16 μg/ml) 70,195 (0) 203,633 (0) 125,440 (0) (0.032 μg/ml) 64,614 (0)173,998 (0) 105,882 (0) Infected + AZT at: (5 μg/ml) 13,542 10,17012,330 (1 μg/ml)  8,705  5,354  6,830 (0.2 μg/ml) 34,360 32,778 31,759(0.04 μg/ml) 23,234 17,144 22,993 (0.008 μg/ml) 42,004 70,380 75,428

TABLE 13 Thera- Sample peutic Identification Purity IC₅₀ (μg/ml) EC₅₀(μg/ml) Index LH70C1-4L (16) +U937 cells pure >4 but <20 0.00128 >3,125but <15,625 +PBMCs pure >4 but <20 0.018 >222 but <1,111

The effect of compound 16 was tested on HIV-1 infected U937 cells andPBMCs (Table 13).

As part of efforts to biologically characterize 16 the monocytic cellline, U937 and peripheral blood mononuclear cells (PBMCs) wereseparately infected with HIV-1 and then had various concentrations ofthe analog added for 4 days of culture. As shown in table 12, there wassuppression detected with both types of cellular infections.

EXAMPLE VI Suksdorfin Analog Purification and Activity Chemistry

Suksdorf in 1 was obtained according to Example I. Suksdorf in was alsoisolated previously from the roots of Angelica Moril Hayata (Shan DuHuo), a drug of folk remedy in Taiwan (Hata, et al., Chem.Pharm.Cull.1974, 22, 957).

Biological Results

Suksdorf in 1 suppressed virus replication in acutely HIV-l (IIIBisolate) infected H₉ cells as presented in Example I. Compound I alsosuppressed acute HIV-1 replication in fresh peripheral blood mononuclearcells (a T cell infection) with an EC₅₀ value of 3.9 μM and in U937cells (a promonocytic cell line) with an EC₅₀ value of 1.5 μM.

When compound 1 was added for 72 hours to the chronically HIV-1 infectedT cell line, ACH-2, and to the chronically HIV-1 infected promonocyticcell line, U1, there was no increase in the induction of virusexpression from either cell line. Even when both chronically HIV-1infected cell lines were cultured in the presence of a known virusinducer such as the phorbol ester, PMA (phorbol 12-myristate13-acetate), there was no alteration in the level of virus expression(Table 3). In addition, compound 1 was found to potentiate the anti-HIVeffects of three nucleosides AZT, ddi, and ddc. Combination of 4 μg/mlof 1 with these nucleosides reduced their EC₅₀ values by 40-fold (forddc), 400-fold (for AZT), and 4000-fold (for ddi) (Table 15).

As shown in Table 1, only 1 showed potent anti-HIV-1 activity atnontoxic concentrations. All other compounds (2-11) were either inactiveor were less active and more toxic. The furanocoumarins (3-10) wereinactive or active only at toxic concentrations (e.g., the therapeuticindex of 4 was 1.3). The dicoumaryl ether 11 showed no activity.

Discussion

The inhibition of virus replication mediated by suksdorf in 1 in both T(H₉) and promonocytic (U937) cell line acute HIV-1 infections designatesthis compound as a lead structure in a new class of potential anti-HIVagents. To further demonstrate suksdorf in's broad cellular specificityand potential clinical relevance, HIV-1 replication in freshPHA-stimulated PBMCs (T cell) was found also to be suppressed in itspresence The absence of increased levels of viral replication inchronically infected cells treated with compound 1 suggests that itwould not increase the in vivo replication of HIV in a patient who islatently infected. The synergistic effects of compound 1 with thereverse transcriptase inhibitors AZT, ddi, and ddc are significantresults demonstrating that compound 1 and analogs accord to formulae(I)-(XX) are expected to have increased anti-HIV activity and/ordecreased toxicity of these known nucleoside drugs. In the preliminarystructure-activity relationship study, the 4′-isovaleryl group of 1 wasimportant for selective HIV-1 inhibition. Replacement of this group withan angeloyl moiety as in pteryxn compound 2 increased the toxicity by-fold and slightly reduced anti-HIV-1 activity.

In summary, suksdorfin analogs as compounds according to formulae(I)-(XX) are expected to be useful for chemotherapy of HIV infectionand/or AIDS, either alone or in combination with FDA-approvednucleosides. Preliminary in vitro results have shown good anti-HIVactivities in a variety of cell lines.

Experimental Section

Chemistry

Isolation of Suksdorfin as presented herein, in Examples I-VI, TheLomatium suksdorfii plant used was collected in Washington state. Theground, air-dried fruits (100 g) were extracted with MeOH. The activeMeOH extract was partitioned between hexane and 90t MeOH (1:1).Evaporation of the active hexane extract gave a crystalline residue.Recrystallization of this residue with hexane yielded 1 as colorlessneedles (1 g, 1i yield): mp 140-141° [α]_(D) ²⁴ +40 (c 0.5, EtOH). TheIR and NMR data of compound 1 are identical to those reported (Willette,et al. J.Pharm.Sci. 1962, 51, 149) (Hata, et al., Chem.Pharm.Cull. 1974,22, 957) for suksdorfin, which was previously isolated from this samespecies.(Willette, et al. J.Pharm.Sci. 1962, 51, 149)

Suksdorfin-related Coumarins

Compounds 2 (pteryxin), (Lee, et al., J. Pharm. Sci. 1968, 57, 865) 3(columbianadin), (Soine, et al., J. Pharm. Sci. 1967, 56, 655)(Willette, et al. J. Pharm. Sci. 1964, 53, 275) 4 (nodakenetin), (Lee,et al., J.Pharm.Sci. 1969, 58, 675) 5 (nodakenin), (Lee, et al.,J.Pharm.Sci. 1969, 58, 675) 6 ) (acetyl nodakenin), (Lee, et al.,J.Pharm.Sci. 1969, 58, 675) 7 (imperatorin), (Lee, et al., J.Pharm.Sci.1969, 58, 675) 8 (bergapten), (Lee, et al., J. Pharm.Sci. 1969, 58, 681)9 (isoimperatorin), (Lee, et al., J.Pharm.Sci. 1969, 58, 675) 10(oxypeucedanin), (Lee, et al., J.Pharm.Sci. 1969, 58, 675) and 11(daphnoretin) (Lee, et al., J. Nat. Prod. 1981, 44, 530) were obtainedaccording to published methods.

Biology

Chronically HIV-1 infected cell lines. HIV-1 chronically infected T cellline, ACH-2¹², and HIV-1 chronically infected promonocytic cell line, U113, were continuously maintained in RPMI 1640 with 10% fetal calf serum(FCS). For experiments, the cell lines were only used in the low phaseof growth. Cells (0.5×10⁶ cells/well) and either various concentrationsof suksdorfin or medium alone were added to 24-well plates in thepresence or absence of PMA (10⁻⁸ M). After 72 hours at 37° C. and 5%CO₂, an aliquot of the cell-free supernatants were collected andanalyzed for p24 antigen by ELISA (see below for details of p24 antigenELISA).

HIV Growth Inhibition Assay: The T cell line, H₉, and the promonocyticcell line, U937, were maintained separately in continuous culture withcomplete medium (RPMI 1640 and 10l fetal calf serum (FCS) at 5% CO₂and37° C. Cell lines were used in experiments only when in log phase ofgrowth; whereas, uninfected peripheral blood mononuclear cells (PBMCs)were first stimulated with PHA (1 μg/ml) for 3 days. All cell targetswere incubated with HIV-1 (IIIB isolate, TCID₅₀ 10 ⁴ IU/mi, at amultiplicity of infection of 0.1-0.01 IU/cell) for 1 hour at 37° C. and5% CO₂. The cell lines and PBMCs were washed thoroughly to removeunabsorbed virions and resuspended at 4×10⁵ cells/ml in complete mediumor complete medium with 10% v/v interleukin (Pettinato, et al. J. Amer.Pharm. Asso. 1959, 48, 423) IL-2, respectively. Aliquots ( ml) wereplaced in wells of 24-well culture plates containing an equal volume oftest compound (diluted in the appropriate culture medium). Afterincubation for 4 days at 37° C., cell density of uninfected cultures wasdetermined by counting cells in a Coulter counter to assess toxicity ofthe test compound. A p24 antigen ELISA assay was used to determine thelevel of virus released in the medium of the HIV-infected cultures. Thep24 antigen assay uses a HIV-1 anti-p24 specific monoclonal antibody asthe capture antibody coated-on 96-well plates. Following a sampleincubation period, rabbit serum containing antibodies for HIV-1 p24 isused to tag any p24 “captured” onto the microtiter well surface.Peroxidase conjugated goat anti-rabbit serum is then used to tag HIV-1p24 specific rabbit antibodies which have complexed with captured p24.The presence of p24 in test samples is then revealed by addition ofsubstrate. The cut-off for the p24 ELISA assay is 12. pg/ml. P24 in theculture medium was quantitated against a standard curve containing knownamounts of p24. The effective (EC₅₀) and inhibitory (IC₅₀)concentrations (for anti-HIV activity and cytotoxicity, respectively)were determined graphically. Both the EC₅₀ and IC₅₀ values werecalculated by plotting drug concentration versus percent inhibition, andthen identifying a 50% inhibition value from the graph.

Combination Study: The experimental design is identical to the growthinhibition assay except that various concentrations of AZT, ddI or ddCwere also added to cultures of acutely HIV-1 infected H₉ cells thateither have or have no received different concentrations of suksdorfin.The concentrations of AZT, ddI and ddC were 5 ten-fold dilutionsstarting at 1 μg/ml.

TABLE 14 HIV Inhibition of HIV-1 Replication in H9 Lymphocytes bySuksdorfin 1 and Related Compounds 2-11. Therapeutic Compound IC₅₀(μM)^(a) IC₅₀ (μM)^(b) Index 1 Suksdorfin >52.0 1.3 >40.0 2Pteryxin >10.4 4.6 >3.7 3 Columbianadin >6.1 4.6 >1.3 4 NodakenetinND^(c) Inactive^(d) ND 5 Nodakenin ND Inactive ND 6 Acetyl Nodakenin NDInactive ND 7 Impratorin >74.1 11.1 >6.7 8 Bergapten >92.6 30.1 >3.1 9Isoimperatorin >185.2 40.7 >4.6 10 Oxypeucedanin >69.9 31.5 >2.2 11Daphnoretin ND Inactive ND ^(a)Concentration which inhibits uninfectedcell growth by 50% ^(b)Concentration which inhibits viral replication by50% ^(c)ND = not determined ^(d)No suppression of HIV-1 replication inH9 cells

TABLE 15 Inhibition of HIV-1 Replication in ACH-2 and U1 Cells bySuksdorfin 1 Suksdorfin Concentra- ACH-2 Cells^(a) U 1 Cells^(b) tion−PMA^(c) +PMA^(d) −PMA +PMA 0 μg/ml 3,676 pg/ml 52,122 pg/ml 0 pg/ml6,963 pg/ml 20 μg/ml 4,541 pg/ml 49,914 pg/ml 0 pg/ml 5,096 pg/ml 4μg/ml 4,723 pg/ml 61,235 pg/ml 0 pg/ml 9,728 pg/ml 0.8 μg/ml 3,821 pg/ml55,910 pg/ml 0 pg/ml 7,360 pg/ml 0.16 μg/ml 3,688 pg/ml 50,775 pg/ml 0pg/ml 6,611 pg/ml ^(a)Chronically HIV-1 infected T cell line^(b)Chronically HIV-1 infected promonocytic cell line ^(c)p24 antigenlevel after 72 hours in culture ^(d)PMA 10⁻⁸ M

TABLE 16 Inhibition of HIV-1 replication in H9 Lymphocytic Cells byCombination of Suksdorfin 1 and ATZ, ddI, and ddC. Compound IC₅₀(μM)^(a) IC₅₀ (μM)^(b) Therapeutic Index Suksdorfin >4 but <20 2.8 >1.4but <7.1 AZT >1 0.04 >25 ddI >1 0.4 >2.5 ddC >1 0.004 >250 4 μg/ml >1<0.0001 >10,000 Suksdorfin + AZT 4 μg/ml >1 <0.0001 >10,000 Suksdorfin +ddI 4 μg/ml >1 <0.0001 >10,000 Suksdorfin + ddC ^(a)Concentration whichinhibits uninfected cell growth by 50% ^(b)Concentration which inhibitsviral replication by 50%

EXAMPLE VII Suksdorfin Analog Synthesis and Activity

Recently, much effort has been focused on the search for compoundseffective in the inhibition of HIV, the etiologic agent of AIDS. Theresult has been the identification of numerous inhibitors of HIV reversetranscriptase (RT) nd HIV protease. These include nucleoside analogs andpeptide mimics, respectively. Although the RT inhibitors, such as AZT,ddI, and ddC, are available as anti-AIDS drugs, their clinicaleffectiveness i limited by their toxicity as well as the development ofdrug resistant virus. The discovery and development of a new class ofanti-HIV agents with structures and mechanisms of action different fromthose of nucleoside analogs mentioned above are of current interest.

In the course of our continuing search for novel anti-HIV agents fromnatural products, suksdorfin compound 1 was isolated as an activeprinciple from the fruits of Lomatium suksdorfii (Umbelliferae) e.g., aspresented in Example VI. Compound 1 exhibited inhibitory activityagainst HIV-1 replication in acutely infected H₉ lymphocytes with anEC₅₀ value of 1.3 μM and a therapeutic index of >40. Moreover, compound1 was found to demonstrate a synergistic effect against HIV replicationwhen it was co-administered with either AZT, ddl, or ddC (data notshown). This discovery has prompted our synthesis of the dihydroseselintype pyranocoumarin derivatives (compounds 2-5) as a new class ofanti-HIV agents.

The synthesis of 2-5 is shown in Scheme 1 as present in Example IV.Seselin compound 7 was prepared from the commercially available7-hydroxycoumarin 6 according to a procedure reported in the literature.(Hlubuek, et al., Aust. J. Chem., 1971, 62, 2347-2354) Subsequentoxidation (El-Antably, et al., J. Pharm. Sci., (1973) 62 1643-1648) ofcompound 7 with OSO₄ gave the racemic cis-khellactone compound 8.Alternatively, compound 7 was treated with m-chloroperbenzoic acid(Schroeder, et al., Chem.Ber., 1959, 93, 93 2388-2363) to furnish4′-O-m-chlorobenzoyl- (+/−) -trans-khellactone 9, which was thenhydrolyzed to produce the racemic trans-khellactone 10. Treatment of 8and 10 with (−)-camphanoyl chloride (Gerlach, et al., J. Chem. Soc.,Chem. Commun., 1973, 274-275) afforded diastereoisomers in each case.The diastereoisomers were separated by repeated column chromatography toyield four isomers of di-O-(−)-campanoylkhellactone (2-5).

The stereochemistries of 2-5 were assigned as follows: the naturallyoccurring di-O-acyl- (+) -cis-khellactone (e.g., 11) was hydrolyzed withbase to give (+)-cis-11 as well as (−)-trans-12 khellactones. (Willette,et al., J.Phaxm.Sci. 1962, 51, 149-156) -Treatment of 11 and 12 with(−)-camphanoyl chloride afforded their corresponding diesters, whichwere found to be identical with 2 and 4, respectively, by directspectral comparison (Scheme 3).

As shown in Table 17, compound 2 demonstrated extremely potentinhibitory activity against HIV-1 replication in acutely infected H₉lymphocytes with an EC₅₀ value of 0.00041 μM. The IC₅₀ range againstuninfected H₉ cell growth was >32 but <160 μM, which was less toxic thanthe active principle (compound 1). The therapeutic index for 2was >78,049 but <390,244. Since the EC₅₀ value and the therapeutic indexof AZT in this assay system are 0.15 μM and 12,500, respectively,compound 2 is more potent than AZT as an anti-HIV agent.

Compound 3, the diastereoisomer of 2, as well as the trans-khellactonederivatives with same acyl groups (4 and 5) showed much less anti-HIVactivity than 2. Since only 1 and 2 show potent anti-HIV activity andboth contain the same configuration at C-3′ and C-4′, the(+)-cis-khellactone skeleton can be required for the enhanced anti-HIVactivity.

In order to determine whether the anti-HIV activity of 2 was limited toacute HIV-1 infections of the T cell line, H₉, both PHA-stimulatedperipheral blood mononuclear cells (PBMCs) and the promonocytic cellline, U937, were separately infected with HIV-1. The results showed thatthere was suppression detected no matter which type of target cell wasused. This indicates that compound 2 was an effective suppressor ofvirus replication no matter if fresh T cells (PBMCs) or a T cell line(H₉) was used or a monocytic cell (U937) was infected with HIV-1. TheEC₅₀ value and the therapeutic index against PBMCs were 0.029 μMand >222 but <1,111, while those against U937 were 0.0021 μM and >3,125but <15,625.

Studies on the mechanism of action for 1, 2 and other related compoundsare in progress.

In conclusion, compound 2 and its related compounds, such as 1,represent a new class of potent anti-HIV agents, which are structurallyunique compared with other known anti-AIDS drugs.

TABLE 17 HIV Inhibition by Di-O-(-)-camphanoylkhellactones (2-5),Suksdorfin 1, and AZT Compounds IC₅₀ (μM) EC₅₀ (μM) Therapeutic Index2 >32 but <160 0.00041 >78,049 but <390,244 3 1,700 51 >33.3 4 >6.4 but<32 >6.4 but <32 >1 5 >32 32 >1 Suksdorfin1 >52 1.3 >40 AZT 1,875 0.1512,500

Detailed Analytical Data for 2-5

3′,4′-Di-O-(−)-Camphanoyl-(+)-cis-Khellactone (2): Colorless needles(from EtOH); mp 200-202° C.; [α]D/20+31.1° (c-0.5, CHCl₃); Positive FABMS m/z 623 (M+H)+, 425 (M-camphanic acid)+, 227 (M-2xcamphanic acid)+;IR (KBr) 1790, 1745 (COO), 1605 (C+C); 1H NMR (300 MHz, CDCl₃ ? 7.62(1H, d, J=9.5 Hz, H-4), 7.41 (1H, d, J=8.5 Hz, H-5), 6.82 (1H, d, J=8.5Hz, H-6), 6.66 (1H, d, J=5 Hz, H-4′), 6.24 (1H, d, J=9.5 Hz, H-3), 5.39(1H, d, J=5 Hz, H-3′), 2.50, 2.23, 1.94, 1.70 (each 2H, m, camphanoylCH₂), 1.50, 1.45 (each 3H, s, 2′-CH₃), 1.12, 1.11, 1.10, 1.08, 1.01,0.98 (each 3H, s, camphanoyl CH₃). Anal. Calcd for C₃₄H₃O₁₁:CF, 65.58;H, 6.15. Found: C, 65.41; H, 6.21.

3′,4′-Di-O-(−)-Camphanoyl-(−)-cis-Khellactone (3): Colorless needles(from EtOH); mp242-244° C.; [α]D/20−67.7° (c=0.5, C:-:C1₃); Positive F3Ms in/z 623 (M+H)+, 425 (M-camphanic acid)+, 227 (M-2xcamphanic acid)+;IR (KBr) 1780, 1750 (COO), 1605 (C=C); 1H NMR (300 MHz, CDCl₃? 7.61 (1H,d, J=9.5 Hz, H-4), 7.40 (1H, d, J=8.5 Hz, H-5), 6.82 (1H, d, J=8.5 Hz,H-6), 6.74 (1H, d, J=4.5 Hz, H-4′), 6.22 (1H, d, J=9.5 Hz, H-3), 5.47(1H), d, J=4.5 Hz, H-3′), 2.55, 2.34, 2.10, 1.93, 1.70 (8H in total,each m, camphanoyl CH₂), 1.56, 1.45 (each 3H, s, 2′-CH₃), 1.13, 1.12,1.06, 1.04, 0.94 (18H in total, each s, camphanoyl CH₃). Anal. Calcd forC₃₄H₃O₁₁CF, 65.58; H, 6.15. Found: C, 65.46; H, 6.12.

31′4′-Di-O-(−)-Camphanoyl-(−)-trans-Khellactone (4): Colorless needles(from EtOH); mp249-251° C; [α]D/20+18.4° (c=0.5, CHCl₃); Positive FAB MSm/z 623 (M+H)+, 425 (M-camphanic acid)+, 227 (M-2xcamphanic acid)+; IR(XBr) 1790, 1770, 1750 (COO), 1610 (C═C); 1H NMR (300 MHz, CDCl₃) ? 7.63(1H, d, J=9.5 Hz, H-4), 7.42 (1H, d, J8.5 Hz, H-5), 6.86 (1H, d, J=8.5Hz, H-6), 6.30 (1H, d, J=3.5 Hz, H-4′), 6.24 (1H, d, J=9.5 Hz, H-3),5.39 (1H, d, J=3.5 Hz, H-3′), 2.50, 2.46, 2.07, 1.93, 1.66 (8H in total,each m, camphanoyl CH₂), 1.50, 1.41 (each 3H, s, 2′-CH₃), 1.12, 1.09,1.08, 1.00, 0.98, 0.97 (each 3H, 9, camphanoyl CH₃). Anal. Calcd forC₃₄H₃₈O₁₁:CF, 65.58; H, 6.15. Found: C, 65.60; H, 6.17.

3′, 4′-Di-O-(−)-Camphanoyl-(+)-trans-Khellactone (5): Colorless needles(from EtOH); mp253-254° C.; [α]D/20−42.0° (c=0.5, CHCl₃); Positive FABMS m/z 623 (M+H)+, 425 (M-camphanic acid)+, 227 (M-2xcamphanic acid)+;IR (KBr) 1800, 1750, 1735, (COO), 1605 (C═C); 1H NMR (300 MHz, CDCl₃) ?7.64 (1H, d, J=9.5 Hz, H-4), 7.41 (1H, d, J=8.5 Hz, H-5), 6.84 (1H, d,J=8.5 Hz, H-6), 6.29 (1H, d, J=3.5 Hz, H-4′), 6.26 (1H, d, J=9.5 Hz,H-3), 5.40 (1H, d, J=3.5 Hz, H-3′), 2.49, 2.12, 1.92, 1.68 (each 2H, m,camphanoyl CH₂), 1.50, 1.41 (each 3H, s, 2′-CH₃), 1.10, 1.09, 1.07,1.06, 0.99, (18H in total, each s, camphanoyl CH₃). Anal. Calcd forC₃₄H₃₈O₁₁:CF, 65.58; H, 6.15. Found: C, 65.66; H, 6.19.

All references cited herein, including journal articles or abstracts,published or corresponding U.S. or foreign patent applications, issuedU.S. or foreign patents, or any other references, are entirelyincorporated by reference herein, including all data, tables, figures,and text presented in the cited references. Additionally, the entirecontents of the references cited within the references cited herein arealso entirely incorporated by reference.

Reference to known method steps, conventional methods steps, knownmethods or conventional methods is not in any way an admission that anyaspect, description or embodiment of the present invention is disclosed,taught or suggested in the relevant art.

The foregoing description of the specific embodiments will so fullyreveal the general nature of the invention that others can, by applyingknowledge within the skill of the art (including the contents of thereferences cited herein), readily modify and/or adapt for variousapplications such specific embodiments, without undue experimentation,without departing from the general concept of the present invention.Therefore, such adaptations and modifications are intended to be withinthe meaning and range of equivalents of the disclosed embodiments, basedon the teaching and guidance presented herein. It is to be understoodthat the phraseology or terminology herein is for the purpose ofdescription and not of limitation, such that the terminology orphraseology of the present specification is to be interpreted by theskilled artisan in light of the teachings and guidance presented herein,in combination with the knowledge of one of ordinary skill in the art.

What is claimed is:
 1. A compound according to formula (IV):

wherein M is O or NH; Z is O, NH or S; R²⁰, R²¹, R²², R²³, R²⁴, are eachH, halogen, OH, O-alkyl, O-acyl, NH₂, NH-alkyl, N-(alkyl)₂, CF₃, OCF₃ orCH₂CONH-alkyl; R₂₅ and R²⁶ are each H, C₁₋₁₀ alkyl, C₁₋₁₀acyl, aryl,COCF₃, amide or CH₃COOR²⁶, where R¹⁶ is C₁₋₁₀alkyl, C₁₋₁₀acyl, or arylor (+) - camphanoyl or (−) -camphanoyl; wherein the bond between C3 andC4 can be double or single; configurations at 3′ or 4′ can be (R) or(S); and R²⁵ and R²⁶ can be oriented cis-β or cis-α, or trans-3′-β ortrans-3′-α.
 2. A compound according to claim 1, wherein C3 and C4 form adouble bond or single bond.
 3. A compound according to claim 1, whereinsaid compound is selected from the group consisting of (IV-A), (IV-B),(IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (IV-I), (IV-J), (IV-K),(IV-L), (IV-M), (IV-N), (IV-O), (IV-P), (IV-Q), (IV-R), (IV-S), (IV-T),(IV-U), (IV-I), (IV-W), (IV-X), (IV-Y), (IV-Z) and isomers thereof.
 4. Acompound according to claim 3, wherein said compound is an isomer of(IV-P).
 5. A compound according to formula (V):

wherein M is O or NH; X and Z═O, NH or S; R²⁸, R²⁹, R³⁰, R³¹ and R³² areeach H, halogen, OH, O-alkyl, O-acyl, NH₂, NH-alkyl, N-(alkyl)₂, CF₃,OCF₃ or CH₂CONH-alkyl; R³³ and R³⁴ are each H, C₁₋₁₀ alkyl, C₁₋₁₀acyl,aryl, COCF₃, amide or CH₂COO R³⁵, where R³⁵ is C₁₋₁₀ alkyl, C₁₋₁₀ acyl,or aryl or (+) -camphanoyl or (−) -camphanoyl and where the bond betweenC3 and C4 can be double or single; configurations at 3′ or 4′ can be (R)or (S); and R³³ and R³⁴ can be oriented cis-β or cis-α or trans-3′-β ortrans-3′-α.
 6. A compound according to claim 5, wherein said compound isselected from the croup consisting of (V-A), (V-B), (V-C), (V-D), (V-E),(V-F), (V-G), (V-H), (V-I), (V-J), (V-K), (V-L), (V-M), (V-N), (V-O),(V-P), (V-Q), (V-R), (V-S), (V-T), (V-U), (V—V), (V-W), (V-X), (V-Y),(V-Z) and isomers thereof.
 7. A compound according to claim 6, whereinsaid compound is an isomer of (V-P) .
 8. A compound having the formula:

wherein M is O or NH; X and Z are O; Y is O, NH or S; R¹³, R¹⁵ and R¹⁶are independently hydrogen, halogen, hydroxy, alkoxy, acyloxy, amino,monoalkylamino, dialkylamino, trifluoromethyl, trifluoromethoxy or—CH₂CONH-alkyl; R¹⁴ is hydrogen, halogen, hydroxy, alkyl, alkoxy,acyloxy, amino, monoalkylamino, dialkylamino, trifluoromethyl,trifluoromethoxy or —CH₂CONH-alkyl; R¹⁷ and R¹⁸ are independentlyhydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ acyl, camphanoyl, aryl,trifluoromethylcarbonyl, amide or —CH₂COOR¹⁹, where R¹⁹ is C₁₋₁₀ alkylor aryl; and where the configurations at 3′ or 4′ can be (R) or (S); andR¹⁷ and R¹⁸ can be oriented cis-β cis-α, trans-3′-β or trans-3′-α; withthe proviso that when M, X, Y and Z are each O and R¹³, R¹⁴, R¹⁵ and R¹⁶are each hydrogen, then R¹⁷ or R¹⁸ are each other than hydrogen, C₁₋₁₀acyl or C₁₋₁₀ alkyl.
 9. A compound according to claim 8, wherein X, M, Yand Z are each oxygen; and R¹⁷ and R¹⁸ are both (+)-camphanoyl or(−)-camphanoyl.
 10. A compound according to claim 8, wherein M is O; Xand Z are O; and Y is S.
 11. A pharmaceutical composition comprising acompound according to claim 8 or a pharmaceutically acceptable ester,ether, sulfate, carbonate, glucuronide or sale thereof, and apharmaceutically acceptable carrier.
 12. A pharmaceutical compositionaccording to claim 11, further comprising a drug selected from anantiviral agent or an immunostimulating agent.
 13. A compositionaccording to claim 12, wherein said antiviral agent is selected from thegroup consisting of gamma globulin, amantadine, guanidine,hydroxybenzimidazole, interferon-α, interferon-β, interferon-γ,thiosemicarbazones, methisazone, rifampin, ribavirin, a pyrimidineanalog, a purine analog, foscarnet, phosphonoacetic acid, acyclovir,dideoxynucleosides and ganciclovir.
 14. A method for inhibiting aretroviral infection in cells or tissue of an animal, comprisingadministering an effective retroviral inhibiting amount of a compoundaccording to formula (III):

wherein M is O or NH; X and Z are O; Y is O, NH or S; R¹³, R¹⁵ and R¹⁶are independently hydrogen, halogen, hydroxy, alkoxy, acyloxy, amino,monoalkylamino, dialkylamino, trifluoromethyl, trifluoromethoxy or—CH₂CONH-alkyl; R¹⁴ is hydrogen, halogen, hydroxy, alkyl, alkoxy,acyloxy, amino, monoalkylamino, dialkylamino, trifluoromethyl,trifluoromethoxy or —CH₂CONH-alkyl; R¹⁷ and R¹⁸ are independentlyhydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ acyl, camphanoyl, aryl,trifluoromethylcarbonyl, amide, or —CH₂COOR⁹, where R¹⁹ is C₁₋₁₀ alkylor aryl, and where the configurations at 3′ or 4′ can be (R) or (S); andR¹⁷ and R¹⁸ can be oriented cis-β, cis-α, trans-3′-β or trans-3′-α. 15.The method according to claim 14, wherein X, M, Y and Z are each oxygenand R¹⁷ and R¹⁸ are both (+)-camphanoyl or (−)camphanoyl.
 16. The methodaccording to claim 15, wherein M is O; X and Z are O; and Y is S. 17.The method according to claim 16, wherein R¹³ is hydrogen and R¹⁷ andR¹⁸ are each (−)-camphanoyl.
 18. A method for treating a patientsuffering from a retroviral related pathology, comprising administeringto said patient an effective retroviral inhibiting amount of a compoundaccording to formula (Ill):

wherein M is O or NH; X and Z are O; Y is O, NH or S; R¹³, R¹⁵ and R¹⁶are independently hydrogen, halogen, hydroxy, alkoxy, acyloxy, amino,monoalkylamino, dialkylamino, trifluoromethyl, trifluoromethoxy orCH₂CONH-alkyl; R¹⁴ is hydrogen, halogen, hydroxy, alkyl, alkoxy,acyloxy, amino, monoalkylamino, dialkylamino, trifluoromethyl,trifluoromethoxy or —CH₂CONH-alkyl; R¹⁷ and R¹⁸ are independentlyhydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ acyl, aryl, trifluoromethylcarhonyl,carbamoyl, camphanoyl, or —CH₂COOR¹⁹, where R¹⁹ is C₁₋₁₀ alkyl or aryl;and where the configurations at 3′ or 4′ can be (R) or (S); and R¹⁷ andR¹⁸ can be oriented cis-β, cis-α, trans-3′-β or trans-3′-α.